Therapeutic uses of tri-, tetra-, penta-, and polypeptides

ABSTRACT

Novel uses of certain peptides to treat patients suffering from neurological or psychiatric disorders are disclosed. The peptides include the tripeptide hormone MIF and compounds made by modifications of MIF, such as modification of amino terminus residues, carboxyl terminus residues and internal residues, including addition and substitution of amino acid residues and modification of the peptide bonds and functional side groups of respective amino acid residues. The tri-, tetra-, penta-, peptides and polypeptides may be utilized alone or in combination with other agents, to treat patients suffering from physiological, psychosomatic, neurological or psychiatric disorders.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application is a continuation-in-part of U.S. patentapplication Ser. No. 09/625,103 filed Jul. 25, 2000, which is acontinuation-in-part of U.S. patent application Ser. No. 08/962,962filed Nov. 4, 1997, now U.S. Pat. No. 6,093,797, which is acontinuation-in-part of U.S. patent application Ser. No. 08/432,651filed on May 2, 1995, now U.S. Pat. No. 5,767,083, which is acontinuation-in-part of U.S. patent application Ser. No. 08/238,089filed on May 4, 1994, now U.S. Pat. No. 5,589,460. The disclosures ofeach of U.S. Pat. Nos. 6,093,797; 5,767,083; and 5,589,460 are herebyincorporated herein by reference in their entirety.

FIELD OF THE INVENTION

[0002] The present invention is related to methods for treating patientssuffering from physiological, psychosomatic, neurological or psychiatricdisorders. The methods include the administration of certain peptides.

BACKGROUND OF THE INVENTION

[0003] Endogenous depression is thought to be a genetically determinedbiochemical disorder which can result in an inability to deal withstress. Treatment for endogenous depression includes electroconvulsivetherapy and/or drug therapy. Drugs administered for therapeutictreatment of depression include tricyclic antidepressants, monoamineoxidase (MAO) inhibitors, “second-generation” antidepressants, andselective serotonin reuptake inhibitors (SSRIs).

[0004] Tricyclic antidepressants (TPAs) have been the drug of firstchoice in treating endogenous depression for over three decades.However, these drugs have limited efficacy in that 40 to 60% of patientsreceiving tricyclic drugs do not respond favorably. The side effects ofthe tricyclics are numerous, including cholinergic blockage, cardiaccomplications, allergic reactions, dry mouth, constipation, blurredvision and tachycardia. Tricyclic antidepressants are characterized by athree-ringed structure, and include imipramine, desipramine,amitriptyline, nortriptyline, protriptyline, doxepin and trimipramine.The tricyclic antidepressants are metabolized through the mixed-functionoxidase system, and the metabolites of the tricyclic antidepressants arealso pharmacologically active compounds.

[0005] The MAO inhibitors have been available for treatment ofdepression since the 1950's. MAO inhibitors are classified either ashydrazides, which contain by a C—N—N moiety (e.g., phenelzine andisocarboxazide) or nonhydrazides (e.g., tranylcypromine). MAO inhibitorshave not gained wide acceptance due to serious side effects.

[0006] The second-generation antidepressants include amoxapine,maprotiline, nefasodone, trazodone and bupropion. The second-generationantipressants a produce a variety of effects on serotonergic anddopaminergic activity.

[0007] The selective serotonin reuptake inhibitors, includingfluoxetine, sertraline, paroxetine, fluoroxamine, and citalopram, arebelieved to work primarily by a serotonergic mechanism. They are saferand better tolerated than the TCAs and MAOIs, but are probably not aseffective in more serious depression and have troublesome side effectssuch as sexual dysfunction in about 40% of patients. In addition, aboutthirty percent of patients do not have a favorable response with theSSRIs.

[0008] The tripeptide MIF, otherwise known as melanocyte stimulatinginhibitory factor, which is represented by the chemical formula ofprolyl-leucyl-glycinamide or Pro-Leu-Gly-NH₂, has been shown to producenumerous non-endocrine effects on the brain. The MIF tripeptide has alsobeen shown to be active in a number of animal models for depression.

[0009] A need remains for new and/or improved methods and compositionsfor treating psychiatric and neurological disorders. In particular, itis desired to provide such new methods and compositions while reducingand preferably minimizing undesired side effects.

SUMMARY OF THE INVENTION

[0010] The present invention provides compositions and methods fortreating physiological, psychosomatic, neurological or psychiatricdisorders. The compositions are peptides. The compositions and methodsare useful in treating patients suffering from neurological orpsychiatric disorders.

[0011] It has been found that peptides described herein are potentiallyuseful in treating a variety of physiological, psychosomatic,neurological and psychological disorders, including bipolar disorder,seasonal affective disorder, eating disorders such as bulimia, anorexianervosa and exogenous obesity, chronic fatigue syndrome, fibromyalgia,sexual dysfunction, anxiety disorders, attention deficit disorder,Parkinson's disease, depression accompanying schizophrenia, jet lagsyndrome and addiction disorders including alcohol dependence. It hasfurther been found that the methods and compositions disclosed hereinare effective in treating depression in patients that are deemedunresponsive to conventional anti-depressant medications. Such patientsmay be referred to as “refractory” patients.

[0012] It has further been found that the methods and compositionsdisclosed herein are useful in treating patients suffering from anxiety.In treating patients suffering from anxiety, the compositions disclosedherein may be administered alone or in combination with otherpharmaceutical compounds.

[0013] According to one aspect of the invention, there is provided amethod for treating a patient suffering from bipolar disorder. Themethod comprises administering to the patient a pharmaceuticallyeffective amount of one or more of the peptides disclosed herein.

[0014] According to another aspect of the invention, there is provided amethod for treating a patient suffering from seasonal affectivedisorder. The method comprises administering to the patient apharmaceutically effective amount of one or more of the peptidesdisclosed herein.

[0015] According to another aspect of the invention, there is provided amethod for treating a patient suffering from an eating disorder. Themethod comprises administering to the patient a pharmaceuticallyeffective amount of one or more of the peptides disclosed herein.

[0016] According to another aspect of the invention, there is provided amethod for treating a patient suffering from fibromyalgia or chronicfatigue syndrome. The method comprises administering to the patient apharmaceutically effective amount of one or more of the peptidesdisclosed herein.

[0017] According to another aspect of the invention, there is provided amethod for treating a patient suffering from sexual dysfunction. Themethod comprises administering to the patient a pharmaceuticallyeffective amount of one or more of the peptides disclosed herein.

[0018] According to one another aspect of the invention, there isprovided a method for treating a patient suffering from anxietydisorder. The method comprises administering to the patient apharmaceutically effective amount of one or more of the peptidesdisclosed herein.

[0019] According to another aspect of the invention, there is provided amethod for treating a patient suffering from attention deficit disorder.The method comprises administering to the patient a pharmaceuticallyeffective amount of one or more of the peptides disclosed herein.

[0020] According to another aspect of the invention, there is provided amethod for treating a patient suffering from Parkinson's disease. Themethod comprises administering to the patient a pharmaceuticallyeffective amount of one or more of the peptides disclosed herein.

[0021] According to another aspect of the invention, there is provided amethod for treating a patient suffering from depression accompanyingschizophrenia. The method comprises administering to the patient apharmaceutically effective amount of one or more of the peptidesdisclosed herein.

[0022] Peptides for use in the methods described herein includecompounds made by modifications, substitutions, additions and/ordeletions to a MIF core structure, Pro-Leu-Gly-NH₂, also referred toherein as “modified MIF compounds”. The modified MIF compounds have beenfound to have pharmacological activity and to be useful in treating avariety of neurological or psychiatric disorders.

[0023] The compounds disclosed herein may be administered by a varietyof routes, including subcutaneously, intramuscularly, orally,sublingually, and transdermally.

DETAILED DESCRIPTION OF THE INVENTION

[0024] Preferred compositions for use in treating neurological orpsychiatric disorders according to the methods described herein arepeptides having selected modifications as compared to MIF. Modificationsmay be introduced, for example, at amino terminus residues, carboxylterminus residues and/or internal residues. Exemplary modificationsinclude addition and substitution of amino acid residues andmodification of the peptide bonds and functional side groups ofrespective amino acid residues as more fully described hereinbelow.

[0025] Unless stated otherwise, the following terms and abbreviationswhen used herein have the meanings set forth below.

[0026] “Carboxyl” means any functional group having the formula —CO₂H or—RCO₂H, wherein R represents a monocyclic organic compound including athree to six member ring, of which at least one member is a nitrogenatom.

[0027] “Hydroxyalkyl” means any functional group having the formula—ROH, where R represents a lower alkyl group, preferably having 1 to 3carbon atoms.

[0028] “Carbamyl” means any functional group having the formula —CONH₂or —RCONH2, wherein R represents a heterocyclic organic compoundincluding a ten member ring, of which at least one member is a nitrogenatom.

[0029] “Alkylcarbamyl” means any functional group having the formulaCONR¹R² wherein R¹ and R² each independently represent a hydrogen atomor a lower alkyl group, preferably having 1 to 3 carbon atoms.

[0030] “Alkoxycarbonyl” means any functional group having the formulaCO₂R, wherein R represents a lower alkyl group, preferably having 1 to 3carbon atoms. dehydro anhydro group where one or more hydrogen atoms areremoved; hydroxyl alcohol group or —OH or —ROH where R represents alower alkyl group, preferably having 1 to 3 carbon atoms; sulphydrylthiol group —SH or —RSH where R represents a lower alkyl group,preferably having 1 to 3 carbon atoms; alkylamino —NHR where Rrepresents a lower alkyl group, preferably having 1 to 3 carbon atoms;dialkylamino —NR₂ where R represents a lower alkyl group, preferablyhaving 1 to 3 carbon atoms; hydroxyamino —NHOH group; patient includesany member of the animal kingdom, including but not solely limited tohumans; and, CGI Control group inactive. Pro L-proline; Leu L-leucine;Gly L-glycine; Tyr L-tyrosine; Ala L-alanine; Arg L-arginine; LysL-lysine; Phe L-phenylalanine; Trp L-tryptophan; Ile L-isoleucine; OrnL-ornithine; D-Arg D-arginine; D-Leu D-leucine; 3,4-dehydro-Pro3,4-dehydro-L-proline; pGlu pyro-glutamic acid; Sar L-sarcosine(N-methylglycine); 4-OH-Pro 4-hydroxyproline; 4-thio-Pro 4-thioproline;2-F-Phe 2-fluorophenylalanine; 3-F-Phe 3-fluorophenylalanine; 4-F-Phe4-fluorophenylalanine; 4-Cl-Phe 4-chlorophenylalanine; 4-NH₂-Phe4-aminophenylalanine; 3(3-pyridyl)Ala 3(3-pyridyl)-alanine Homo-ArgHomo-arginine Homo-Pro Homo-proline Fmoc 9-Fluorenylmethoxycarbonyl; TFAtrifluoroacetic acid;

[0031] One embodiment of the peptides of the present invention includestripeptides characterized by formula (1):

R¹-Pro¹-AA¹-NR²—CH₂—R   (1)

[0032] where Pro¹ represents the amino acid Pro or dehydro-Pro,preferably 3,4-dehydro Pro; AA¹ represents an amino acid of the groupTrp, Orn, Lys, Leu, D-Leu, Arg, D-Arg, or Ile; R represents a carboxylgroup, a hydroxyalkyl group, a carbamyl group, an alkylcarbamyl group,or an alkoxycarbonyl group; R¹ represents a hydrogen atom, a lower alkylgroup, preferably having 1 to 3 carbon atoms, a halogen atom, preferablya fluorine or chlorine atom, a hydroxyl group, a sulphydryl group, or analkylamino or dialkylamino group, preferably a methyl or ethylaminogroup or dimethyl or diethylamino group; and, R² represents a hydrogenatom or a lower alkyl group, preferably having 1 to 3 carbon atoms, withthe proviso that where Pro¹ is Pro and AA¹ is Leu, then R¹ and R² arenot both hydrogen atoms when R is a carbamyl group.

[0033] An embodiment of peptides of formula (1) useful in the treatmentmethods described herein is a tripeptide having formula (1a):

Pro¹-AA¹-Gly-NH₂   (1a)

[0034] wherein Pro¹ and AA¹ are as described above for formula (1).Preferred tripeptides of formula (1a) include Pro-Trp-Gly-NH₂,Pro-Arg-Gly-NH₂, Pro-D-Arg-Gly-NH₂, Pro-Lys-Gly-NH₂, Pro-Orn-Gly-NH₂,and Pro-Ile-Gly-NH₂.

[0035] Another embodiment of tripeptides of formula (1) useful intreating physiological, psychosomatic, neurological or psychiatricdisorders in patients includes compounds having formula (1b):

R¹-Pro¹-AA¹-Gly-NH₂   (1b)

[0036] wherein Pro¹, AA¹ and R¹ are as described above for formula (1).Preferred compositions of the tripeptides of formula (1b) include cis-or trans-4-OH-Pro-D-Arg-Gly-NH₂, cis- or trans-4-OH-Pro-Ile-Gly-NH₂,cis- or trans-4-OH-Pro-Arg-Gly-NH₂, cis- or trans-4-OH-Pro-Trp-Gly-NH₂,and cis- or trans-4-thio-Pro-Leu-Gly-NH₂.

[0037] A further embodiment of tripeptides of formula (1) useful fortreating physiological, psychosomatic, neurological or psychiatricdisorders in patients is formula (1c):

Pro¹-AA¹-NR²-CH₂-R   (1c)

[0038] wherein Pro¹, AA¹, R and R² are as described above for formula(1), with the proviso that where Pro¹ is Pro and AA¹ is Leu, R² is not ahydrogen atom when R is either a carboxyl group or a hydroxyalkyl group,and with the further proviso that where Pro¹ is Pro and AA¹ is Trp, R²is not a hydrogen atom when R is a hydroxyalkyl group. Preferredcompositions of the tripeptides of formula (1c) include, but are notnecessarily limited to Pro-Leu-N(CH₃)CH₂—CONH₂ (or Pro-Leu-Sar-NH₂) andPro-Trp-NHCH₂—CO₂H (or Pro-Trp-Gly).

[0039] In yet a further embodiment, tripeptides useful for utilizationin treating physiological, psychosomatic, neurological or psychiatricdisorders in patients are represented by formula (2):

R¹-Pro¹-AA¹-Ala-R   (2)

[0040] where Pro¹ represents the amino acid Pro or dehydro-Pro,preferably 3,4-dehydro Pro; AA¹ represents an amino acid of the group ofArg or D-Arg; R represents a carboxyl group, a hydroxyalkyl group, acarbamyl group, an alkylcarbamyl group, or an alkoxycarbonyl; and, R¹represents a hydrogen atom, a lower alkyl group, preferably having 1 to3 carbon atoms, a halogen atom, preferably a fluorine or chlorine atom,a hydroxyl group, a sulphydryl group, or an alkylamino or dialkylaminogroup, preferably a methyl or ethylamino or dimethyl or diethylaminogroup.

[0041] An embodiment of the tripeptides of formula (2) disclosed forutilization in treating physiological, psychosomatic, neurological orpsychiatric disorders in patients is represented by formula (2a):

Pro¹-AA¹-Ala-NH₂   (2a)

[0042] wherein Pro¹ and AA¹ are as described above for formula (2).Preferred compositions of the tripeptides of formula (2a) includePro-Arg-Ala-NH₂ and Pro-D-Arg-Ala-NH₂.

[0043] In yet another embodiment, tripeptides of the present inventionuseful in treating physiological, psychosomatic, neurological orpsychiatric disorders in patients are represented by formula (3):

R¹-Pro¹-AA¹-Tyr-R   (3)

[0044] where Pro¹ represents the amino acid Pro or dehydro-Pro,preferably 3,4-dehydro Pro; AA¹ represents the amino acid Orn; Rrepresents a carboxyl group, a hydroxyalkyl group, a carbamyl group, analkylcarbamyl group, or an alkoxycarbonyl group; and, R¹ represents ahydrogen atom, a lower alkyl group, preferably having 1 to 3 carbonatoms, a halogen atom, preferably a fluorine or chlorine atom, ahydroxyl group, a sulphydryl group, or an alkylamino or dialkylaminogroup, preferably a methyl or ethylamino or a dimethyl or diethylaminogroup.

[0045] An embodiment of the tripeptides of formula (3) disclosed forutilization in treating physiological, psychosomatic, neurological orpsychiatric disorders in patients is formula (3a):

R¹-Pro¹-AA¹-Tyr-NH₂   (3a)

[0046] where Pro¹, AA¹ and R¹ are as described for formula (3).Preferred compositions of the tripeptides of formula (3a) includePro-Orn-Tyr-NH₂ and cis- or trans-4-OH-Pro-Orn-Tyr-NH₂.

[0047] The present invention also provides tetrapeptides and use thereofin treating physiological, psychosomatic, neurological or psychiatricdisorders. One embodiment provides tetrapeptide compositions representedby formula (4):

R¹-Pro¹-AA¹-Gly-AA²-R   (4)

[0048] where Pro¹ represents the amino acid Pro or dehydro-Pro,preferably 3,4-dehydro Pro; AA¹ represents Ile, Leu, Arg, D-Arg or Trp;AA² represents an amino acid of the group of Trp or Tyr; R represents acarboxyl group, hydroxyalkyl group, a carbamyl group, an alkylcarbamylgroup, or an alkoxycarbonyl group; and, R¹ represents a hydrogen atom, alower alkyl group, preferably having 1 to 3 carbon atoms, a halogenatom, preferably a fluorine or chlorine atom, a hydroxyl group, asulphydryl group, or an alkylamino or dialkylamino group, preferably amethyl or ethylamino or dimethyl or diethylamino group.

[0049] An embodiment of tetrapeptides of formula (4) useful for treatingphysiological, psychosomatic, neurological or psychiatric disorders inpatients is formula (4a):

R¹-Pro¹-AA¹-Gly-AA²-NH₂   (4a)

[0050] wherein Pro¹, AA¹, AA², and R¹ are as described for formula (4).Preferred compositions of the tetrapeptides of formula (4a) include cis-or trans-4-OH-Pro-Leu-Gly-Trp-NH₂ (SEQ ID NO: 1), cis- ortrans-4-OH-Pro-Ile-Gly-Trp-NH₂ (SEQ ID NO: 2), cis- ortrans-4-OH-Pro-D-Arg-Gly-Trp-NH₂, 3,4-dehydro-Pro-D-Arg-Gly-Trp-NH₂ and3,4-dehydro-Pro-Arg-Gly-Trp-NH2 (SEQ ID NO: 62).

[0051] A further embodiment of tetrapeptides of formula (4) disclosedfor utilization in treating physiological, psychosomatic, neurologicalor psychiatric disorders in patients is formula (4b):

Pro¹-AA¹-Gly-AA²-NH₂   (4b)

[0052] wherein Pro¹, AA¹ and AA² are as described for formula (4).Preferred compositions of the tetrapeptides of formula (4b) includePro-Ile-Gly-Trp-NH₂ (SEQ ID NO: 3), 3,4-dehydro-Pro-Ile-Gly-Trp-NH₂ (SEQID NO: 4), Pro-Leu-Gly-Trp-NH₂ (SEQ ID NO: 5), Pro-Leu-Gly-Tyr-NH₂ (SEQID NO: 6), Pro-Arg-Gly-Trp-NH₂ (SEQ ID NO: 7), Pro-Trp-Gly-Trp-NH₂ (SEQID NO: 8), Pro-D-Arg-Gly-Trp-NH₂, and Pro-Ile-Gly-Tyr-NH₂ (SEQ ID NO:9).

[0053] Another embodiment provides N-terminus end enhanced tetrapeptidecompositions represented by formula (5):

R¹-AA¹-R²-Pro¹-AA²-Gly-R   (5)

[0054] where Pro¹ represents the amino acid Pro or dehydro-Pro,preferably 3,4-dehydro Pro; AA¹ represents an amino acid selected fromTrp, Tyr and Phe; AA² represents an amino acid selected from Leu, Ile,and Trp; R represents a carboxyl group, hydroxyalkyl group, a carbamylgroup, an alkylcarbamyl group, or an alkoxycarbonyl group; and, R¹ andR² each independently represent a hydrogen atom; a lower alkyl group,preferably having 1 to 3 carbon atoms; a halogen atom, preferably afluorine or chlorine atom; a hydroxyl group; a sulphydryl group; or analkylamino or dialkylamino group, preferably a methyl or ethylamino ordimethyl or diethylamino group.

[0055] One embodiment of tetrapeptides of formula (5) useful intreating, physiological, psychosomatic, neurological or psychiatricdisorders in patients is represented by formula (5a):

R¹-AA¹-R²-Pro¹-AA²-Gly-NH₂   (5a)

[0056] wherein Pro¹, AA¹, AA², R¹ and R² are as described for formula(5), with the proviso that where Pro¹ is Pro, R¹ and R² are not bothhydrogen atoms when AA¹ is Tyr and AA² is Trp; and with the furtherproviso that when Pro¹ is Pro, and AA² is Leu, and AA¹ is Phe or Tyr,then R¹ and R² are not both hydrogen atoms. Preferred compositions ofthe tetrapeptides of formula (5a) include Trp-Pro-Leu-Gly-NH₂ (SEQ IDNO: 10), Phe-Pro-Leu-Gly-NH₂ (SEQ ID NO: 11), 4-F-Phe-Pro-Leu-Gly-NH₂(SEQ ID NO: 12), 4-Cl-Phe-Pro-Leu-Gly-NH₂ (SEQ ID NO: 13),4-F-Phe-Pro-Ile-Gly-NH₂ (SEQ ID NO: 14), 4-F-Phe-cis- ortrans-4-OH-Pro-Leu-Gly-NH₂ (SEQ ID NO: 15), 4-F-Phe-cis- ortrans-4-OH-Pro-Ile-Gly-NH₂ (SEQ ID NO: 16), Trp-Pro-Leu-Gly-NH₂ (SEQ IDNO: 17), Trp-Pro-Ile-Gly-NH₂ (SEQ ID NO: 18), Trp-cis- ortrans-4-OH-Pro-Leu-Gly-NH₂ (SEQ ID NO: 19), Trp-cis- ortrans-4-OH-Pro-Ile-Gly-NH₂ (SEQ ID NO: 20), and 4-Cl-Phe-cis- ortrans-4-OH-Pro-Ile-Gly-NH₂ (SEQ ID NO: 60).

[0057] Another embodiment of tetrapeptides of formula (5) useful intreating physiological, psychosomatic, neurological or psychiatricdisorders in patients is formula (5b):

R¹-AA¹-R²-Pro¹-AA²-Gly-R   (5b)

[0058] wherein Pro¹, AA¹, AA², R¹, R² and R are as described for formula(5). Preferred compositions of the tetrapeptides of formula (5b) includecompounds wherein the N-terminus heterocyclic nitrogen ring of Pro¹ isreplaced by a cis- or trans-4-OH— group. In some preferred embodimentsof compositions represented by formula (5b), AA² is Arg. A preferredpeptide of formula (5b) is 4-F-Phe-cis- ortrans-4-OH-Pro-Arg-Gly-1,2,3,4-Tetrahydroisoquinoline-3-carboxamide (SEQNO: 75).

[0059] The present invention further provides pentapeptides and usethereof in treating physiological, psychosomatic, neurological orpsychiatric disorders. One embodiment of the pentapeptides providesN-terminus enhanced pentapeptide compositions represented by formula(6):

R¹-AA¹-AA²-R²-Pro¹-AA³-Gly-R   (6)

[0060] where Pro¹ represents the amino acid Pro or dehydro-Pro,preferably 3,4-dehydro Pro; AA¹ and AA² each independently represent anamino acid of the group of Phe or Tyr; AA³ represents an amino acid ofthe group of Leu or Ile; R represents a carboxyl group, hydroxyalkylgroup, a carbamyl group, an alkylcarbamyl group, or an alkoxycarbonylgroup; and, R¹ and R² each independently represent a hydrogen atom, alower alkyl group, preferably having 1 to 3 carbon atoms, a halogenatom, preferably a fluorine or chlorine atom, a hydroxyl group, asulphydryl group, or an alkylamino or dialkylamino group, preferably amethyl or ethylamino or dimethyl or diethylamino group.

[0061] An embodiment of the pentapeptides of formula (6) useful intreating physiological, psychosomatic, neurological or psychiatricdisorders in patients is formula (6a):

R¹-AA¹-AA²-R²-Pro¹-AA³-Gly-NH₂   (6a)

[0062] wherein Pro¹, AA¹, AA², R¹, and R² are as described for formula(6). Preferred compositions of the pentapeptides of formula (6a) include4-F-Phe-Tyr-Pro-Leu-Gly-NH₂ (SEQ ID NO: 21),4-Cl-Phe-Tyr-Pro-Leu-Gly-NH₂ (SEQ ID NO: 22), Phe-Tyr-Pro-Leu-Gly-NH₂(SEQ ID NO: 23), Phe-Tyr-Pro-Ile-Gly-NH₂ (SEQ ID NO: 24), Phe-Tyr-cis-or trans-4-OH-Pro-Leu-Gly-NH₂ (SEQ ID NO: 25); Phe-Tyr-cis- ortrans-4-OH-Pro-Ile-Gly-NH₂ (SEQ ID NO: 26), Tyr-Tyr-Pro-Leu-Gly-NH₂ (SEQID NO: 27), Tyr-Tyr-Pro-Ile-Gly-NH₂ (SEQ ID NO: 28), Tyr-Tyr-cis- ortrans-4-OH-Pro-Leu-Gly-NH₂ (SEQ ID NO: 29), and Tyr-Tyr-cis- ortrans-4-OH-Pro-Ile-Gly-NH₂ (SEQ ID NO: 30).

[0063] Another embodiment of the pentapeptides provides combinedN-terminus- and C-terminus-enhanced pentapeptide compositionsrepresented by formula (7):

R¹-AA¹-R²-Pro¹-AA²-Gly-AA³-R   (7)

[0064] where Pro¹ represents the amino acid Pro or dehydro-Pro,preferably 3,4-dehydro Pro; AA¹ represents an amino acid of the group ofPhe or Tyr; AA² represents an amino acid of the group of Leu, Ile, Arg,D-Arg, or Trp; AA³ represents the amino acid Trp; R represents acarboxyl group, hydroxyalkyl group, a carbamyl group, an alkylcarbamylgroup, or an alkoxycarbonyl group; and, R¹ and R² each independentlyrepresent a hydrogen atom, a lower alkyl group, preferably having 1 to 3carbon atoms, a halogen atom, preferably a fluorine or chlorine atom, ahydroxyl group, a sulphydryl group, or an alkylamino or dialkylaminogroup, preferably a methyl or ethylamino or dimethyl or diethylaminogroup.

[0065] An embodiment of pentapeptides of formula (7) useful in treatingphysiological, psychosomatic, neurological or psychiatric disorders inpatients is represented by formula (7a):

R¹-AA¹-R²-Pro¹-AA²-Gly-Trp-NH₂   (7a)

[0066] wherein Pro¹, AA¹, AA², R¹ and R² are as described for formula(7). Preferred compositions of the pentapeptides of formula (7a) includePhe-Pro-Leu-Gly-Trp-NH₂ (SEQ ID NO: 31), Tyr-Pro-Leu-Gly-Trp-NH₂ (SEQ IDNO: 32), Phe-cis- or trans-4-OH-Pro-Leu-Gly-Trp-NH₂ (SEQ ID NO: 33),Phe-Pro-Ile-Gly-Trp-NH₂ (SEQ ID NO: 34), Phe-cis- ortrans-4-OH-Pro-Ile-Gly-Trp-NH₂ (SEQ ID NO: 35), Tyr-cis- ortrans-4-OH-Pro-Leu-Gly-Trp-NH₂ (SEQ ID NO: 36), Tyr-Pro-Ile-Gly-Trp-NH₂(SEQ ID NO: 37), Tyr-cis- or trans-4-OH-Pro-Leu-Gly-Trp-NH₂ (SEQ ID NO:38), Tyr-Pro-Trp-Gly-Trp-NH₂ (SEQ ID NO: 39), Tyr-cis- ortrans-4-OH-Pro-Trp-Gly-Trp-NH₂ (SEQ ID NO: 40), 4-F-Phe-cis- ortrans-4-OH-Pro-Ile-Gly-Trp-NH₂ (SEQ ID NO: 41), Phe-cis- ortrans-4-OH-Pro-Leu-Gly-Trp-NH₂ (SEQ ID NO: 42), 4-F-Phe-cis- ortrans-4-OH-Pro-Arg-Gly-Trp-NH₂ (SEQ ID NO: 43), 4-F-Phe-cis- ortrans-4-OH-Pro-D-Arg-Gly-Trp-NH₂, 3-F-Phe-cis- ortrans-4-OH-Pro-Arg-Gly-Trp-NH₂ (SEQ ID NO: 66); 2-F-Phe-cis- ortrans-4-OH-Pro-Arg-Gly-Trp-NH₂ (SEQ ID NO: 68); and 4-Cl-Phe-cis- ortrans-4-OH-Pro-Arg-Gly-Trp-NH₂ (SEQ ID NO: 61).

[0067] Additional preferred compositions of the pentapeptides of formula(7a) are characterized by the optional modification of Pro¹ todehydro-Pro, preferably 3,4-dehydro-Pro. Additional preferred peptidesof formula (7a) include 4-F-Phe-3,4-dehydro-Pro-Ile-Gly-Trp-NH₂ (SEQ IDNO: 72) and 4-F-Phe-3,4-dehydro-Pro-Arg-Gly-Trp-NH₂ (SEQ ID NO: 55).

[0068] Additional preferred pentapeptides of formula (7a) includepentapeptides having modifications at AA², preferably Arg, His,Homo-Arg, L-Allo-Ile or canavanine; additional optional modifications atR¹ and/or R² (preferably R¹) and preferably an amino group, a carboxylgroup, a nitro group, or a phosphono group (preferably asphosphono-Try); additional optional modification of the heterocyclicnitrogen ring of Pro¹, preferably cis- or trans-4-OH or Homo-Pro.Exemplary additional preferred peptides of formula (7a) are4-NH₂-Phe-cis- or trans-4-OH-Pro-Arg-Gly-Trp-NH₂ (SEQ ID NO: 63);4-F-Phe-cis- or trans-4-OH-Pro-His-Gly-Trp-NH₂ (SEQ ID NO: 64);4-NO₂-Phe-cis- or trans-4-OH-Pro-Arg-Gly-Trp-NH₂ (SEQ ID NO: 65);4-CH₃O-Phe-cis- or trans-4-OH-Pro-Arg-Gly-Trp-NH₂ (SEQ ID NO: 59);4-F-Phe-cis- or trans-4-OH-Pro-Homo-Arg-Gly-Trp-NH₂ (SEQ ID NO: 71);4-F-Phe-Homo-Pro-Ile-Gly-Trp-NH₂ (SEQ ID NO: 69);4-F-Phe-Homo-Pro-Arg-Gly-Trp-NH₂ (SEQ ID NO: 57); and 4-F-Phe-cis- ortrans-4-OH-Pro-L-Allo-Ile-Gly-Trp-NH₂ (SEQ ID NO: 73).

[0069] Another embodiment of pentapeptides of formula (7) useful intreating physiological, psychosomatic, neurological or psychiatricdisorders in patients is compounds having formula (7b):

R¹-AA¹-R²-Pro¹-AA²-Gly-Trp-NH₂   (7b)

[0070] wherein AA¹ is Phe; and Pro¹, AA², R¹ and R² are as described forformula (7), with the optional modification of the N-terminusheterocyclic nitrogen ring of Pro¹ with a substituent selected from thegroup consisting of cis-4-OH—, trans-4-OH—, cis-3-OH— and trans-3-OH. Insome embodiments, the pentapeptides may be further modified at R¹,preferably by two or more halogen atoms, or a cyano group. Preferredcompositions of the pentapeptides of formula (7b) include3,4-Dichloro-Phe-cis- or trans-4-OH-Pro-Arg-Gly-Trp-NH₂ (SEQ NO: 76),4-NC-Phe-cis- or trans-4-OH-Pro-Arg-Gly-Trp-NH₂ (SEQ NO: 77),4-F-Phe-cis- or trans-4-OH-Pro-D-Leu-Gly-Trp-NH₂ (SEQ NO: 78),4-F-Phe-trans-3-Hydroxy-Pro-Arg-Gly-Trp-NH₂ (SEQ NO: 79).

[0071] Another embodiment of pentapeptides of formula (7) useful intreating physiological, psychosomatic, neurological or psychiatricdisorders in patients is formula (7c):

R¹-AA¹-R²-Pro¹-AA²-Gly-Trp   (7c)

[0072] wherein Pro¹, AA¹, AA², R¹ and R² are as described for formula(7) with additional optional modifications at AA², preferably Homo-Arg;and additional optional modification of the N-terminus heterocyclicnitrogen ring of Pro¹ with a substituent selected from the groupconsisting of cis-4-OH—, trans-4-OH—, cis-4-OH— and trans-3-OH—. Apreferred composition of the pentapeptides of formula (7c) is4-F-Phe-cis- or trans-4-OH-Pro-Homo-Arg-Gly-Trp (SEQ ID NO: 74).

[0073] Another embodiment of pentapeptides of formula (7) useful intreating physiological, psychosomatic, neurological or psychiatricdisorders in patients is formula (7d):

R¹-AA¹-R²-Pro¹-AA²-Gly-AA³-R   (7d)

[0074] wherein Pro¹, AA¹, AA², AA³, R¹, R² and R are as described forformula (7). In some embodiments, the N-terminus heterocyclic nitrogenring of Pro¹ has a substituent selected from the group consisting ofcis-4-OH—, trans-4-OH—, cis-3-OH—, and trans-3-OH—. In some embodimentsthe pentapeptide is modified at, Pro¹, preferably Homo-Pro. In someembodiments, the pentapeptide is modified at AA¹, preferably PhenylGly.In some embodiments, the peptapeptide is modified at AA³, preferably. Insome embodiments, the pentapeptide is modified at R¹, preferably ahaloform or a methoxyl group. In some embodiments, the pentapeptide ismodified at R, preferably two or more halogen atoms or a hydroxyaminogroup.

[0075] Preferred compositions of the pentapeptides of formula (7d)include 4-CH₃O-Phe-3,4-Dehydro-Pro-Arg-Gly-Trp-NH₂ (SEQ NO: 81),2,4-Di-F-Phe-3,4-Dihydro-Pro-Arg-Gly-Trp-NH₂ (SEQ NO: 82),4-CF₃-Phe-3,4-Dehydro-Pro-Arg-Gly-Trp-NH₂ (SEQ NO: 83),4-F-PhenylGly-3,4-Dehydro-Pro-Arg-Gly-Trp-NH₂ (SEQ NO: 84),3-F-Tyr-3,4-Dehydro-Pro-Arg-Gly-Trp-NH₂ (SEQ NO: 85),4-F-Phe-3,4-Dehydro-Pro-Arg-Gly-Trp-NHOH (SEQ NO: 86),3,4-Di-Cl-Phe-3,4-Dihydro-Pro-Arg-Gly-Trp-NH₂ (SEQ NO: 87),2-F-Tyr-3,4-Dehydro-Pro-Arg-Gly-Trp-NH₂ (SEQ NO: 88),4-F-Phe-3,4-Dehydro-Pro-Arg-Gly-7-AzaTrp-NH₂ (SEQ NO: 89).

[0076] Another embodiment of pentapeptides of formula (7) useful intreating physiological, psychosomatic, neurological or psychiatricdisorders in patients is formula (7e):

R¹-AA¹-R²-Pro¹-AA²-Gly-R⁴-Trp-NH₂   (7e)

[0077] wherein Pro¹, AA¹, AA², R¹ and R² are as described for formula(7). Optionally, the N-terminus heterocyclic nitrogen ring of Pro¹ maybe modified with a substituent selected from the group consisting ofcis-4-OH—, trans-4-OH—, cis-3-OH—, and trans-3-OH—. R⁴ represents amodification of the tryptophan residue at one of C4, C5, C6 and C7 witha halogen atom, a hydroxyl group, or an alkyl group. Preferredcompositions of the pentapeptides of formula (7e) include 4-F-Phe-cis-or trans-4-OH-Pro-Arg-Gly-4-F-Trp-NH₂ (SEQ NO: 107), 4-F-Phe-cis- ortrans-4-OH-Pro-Arg-Gly-7-Methyl-Trp-NH₂ (SEQ NO: 108).

[0078] Another embodiment of pentapeptides of formula (7) useful intreating physiological, psychosomatic, neurological or psychiatricdisorders in patients is formula (7f):

R¹-AA¹-R²-Pro¹-R⁵-AA²-Gly-Trp-NH₂   (7f)

[0079] wherein Pro¹, AA¹, AA², R¹ and R² are as described for formula(7). In some embodiments the N-terminus heterocyclic nitrogen ring ofPro¹ is modified with a substituent selected from the group consistingof cis-4-OH—, trans-4-OH—, cis-3-OH—, and trans-3-OH—. R⁵ represents atleast one halogen atom. A preferred composition of the pentapeptides offormula (7f) is 4-F-Phe-cis- ortrans-4-OH-Pro-5,5,5-Trifluoro-Leu-Gly-Trp-NH₂ (SEQ NO: 109).

[0080] Another embodiment of pentapeptides of formula (7) useful intreating physiological, psychosomatic, neurological or psychiatricdisorders in patients is formula (7g):

R¹-AA¹-R²-Pro¹-AA²-Gly-R⁴-AA³-R   (7g)

[0081] wherein Pro¹, AA¹, AA², AA³, R¹, R² and R are as described forformula (7). In some embodiments, Pro¹ is modified preferably Homo-Pro.In some embodiments, the N-terminus heterocyclic nitrogen ring of Pro¹is modified with a substituent selected from the group consisting ofcis-4-OH—, trans-4-OH—, cis-3-OH—, and trans-3-OH—. R⁴ represents ahalogen atom, a methyl group, a methoxyl group or a hydroxyl group.Preferred compositions of the pentapeptides of formula (7g) include4-F-Phe-3,4-Dehydro-Pro-Arg-Gly-4-F-Trp-NH₂ (SEQ NO: 90),4-F-Phe-3,4-Dehydro-Pro-Arg-Gly-5-F-Trp-NH₂ (SEQ NO: 91),4-F-Phe-3,4-Dihydro-Pro-Arg-Gly- 6-F-Trp-NH₂ (SEQ NO: 92),4-F-Phe-3,4-Dehydro-Pro-Arg-Gly-3-CH₃O-Trp-NH₂ (SEQ NO: 93),4-F-Phe-3,4-Dehydro-Pro-Arg-Gly-N-Methyl-Trp-NH₂ (SEQ NO: 94),4-F-Phe-3,4-Dehydro-Pro-Arg-Gly-1-Methyl-Trp-NH₂ (SEQ NO: 95),4-F-Phe-3,4-Dehydro-Pro-Arg-Gly-4-Methyl-Trp-NH₂ (SEQ NO: 96),4-F-Phe-3,4-Dehydro-Pro-Arg-Gly-5-Methyl-Trp-NH₂ (SEQ NO: 97),4-F-Phe-3,4-Dehydro-Pro-Arg-Gly-6-Methyl-Trp-NH₂ (SEQ NO: 98),4-F-Phe-3,4-Dehydro-Pro-Arg-Gly-5-Hydroxy-Trp-NH₂ (SEQ NO: 99).

[0082] Another embodiment provides internal and C-terminus enhancedpentapeptide compositions represented by formula (8):

R¹-Pro¹-AA¹-AA²-Gly-AA³-R   (8)

[0083] where Pro¹ represents the amino acid Pro or dehydro-Pro,preferably 3,4-dehydro Pro; AA¹ and AA² each independently represent anamino acid of the group of Leu or Ile; AA³ represents the amino acidTrp; R represents a carboxyl group, a hydroxyalkyl group, a carbamylgroup, an alkylcarbamyl group, or an alkoxycarbonyl group; and, R¹represents a hydrogen atom, a lower alkyl group, preferably having 1 to3 carbon atoms, a halogen atom, preferably a fluorine or chlorine atom,a hydroxyl group, a sulphydryl group, or an alkylamino or dialkylaminogroup, preferably a methyl or ethylamino group or dimethyl ordiethylamino group.

[0084] An embodiment of pentapeptides of formula (8) useful in treatingphysiological, psychosomatic, neurological or psychiatric disorders inpatients is represented by formula (8a):

R¹-Pro¹-AA¹-AA²-Gly-Trp-NH₂   (8a)

[0085] wherein Pro¹, AA¹, AA², and R¹ are as described for formula (8).Preferred compositions of the pentapeptides of formula (8a) includePro-Ile-Leu-Gly-Trp-NH₂ (SEQ ID NO: 44) and cis- ortrans-4-OH-Pro-Ile-Leu-Gly-Trp-NH₂ (SEQ ID NO: 45).

[0086] In another embodiment of the invention, pentapeptide compositionsor pharmaceutically acceptable salts thereof including addition of botha N-terminus amino acid and a C-terminus amino acid can be representedby the following formula (9):

R¹-AA¹-R²-Pro¹-AA²-Gly-AA³-R   (9)

[0087] where Pro¹ represents the amino acid Pro or dehydro-Pro,preferably 3,4-dehydro Pro; AA¹ represents the amino acid Ala; AA²represents an amino acid of the group of Leu, Ile, Arg, D-Arg, Trp, orcanavanine; AA³ represents the amino acid Trp; R represents a carboxylgroup, hydroxyalkyl group, a carbamyl group, an alkylcarbamyl group, oran alkoxycarbonyl group; and, R¹ represents a pyridyl ring, preferablyas a 3-(3-pyridyl) moiety; R² represents a hydrogen atom, a lower alkylgroup, preferably having 1 to 3 carbon atoms, a halogen atom, preferablya fluorine or chlorine atom, a hydroxyl group, preferably a cis- ortrans-4-OH— group, a sulphydryl group, preferably a cis- ortrans-4-thio- group, or an alkylamino or dialkylamino group, preferablya methyl or ethylamino or dimethyl or diethylamino group.

[0088] A preferred composition of formula (9) is 3-(3-pyridyl)-Ala-cis-or trans-4-OH-Pro-Arg-Gly-Trp-NH₂ (SEQ ID NO: 70).

[0089] In another embodiment of the invention, hexapeptide compositionsor pharmaceutically acceptable salts thereof including addition of botha N-terminus amino acid and a C-terminus amino acid can be representedby the following formula (10):

R¹-AA¹-R²-Pro¹-AA²-AA⁴-Gly-AA³-R   (10)

[0090] where Pro¹ represents the amino acid Pro or dehydro-Pro; AA¹represents an amino acid of the group of Phe or Tyr; AA² represents anamino acid of the group of Leu, Ile, Arg, D-Arg, Trp, or canavanine; AA³represents the amino acid Trp; AA⁴ represents the amino acid Gly or Ile;R represents a carboxyl group, hydroxyalkyl group, a carbamyl group, analkylcarbamyl group, or an alkoxycarbonyl group; and, R¹ and R² eachindependently represent a hydrogen atom, a lower alkyl group, preferablyhaving 1 to 3 carbon atoms, a halogen atom, preferably a fluorine orchlorine atom, a hydroxyl group, preferably a cis- or trans-4-OH— group,a sulphydryl group, preferably a cis- or trans-4-thio- group, or analkylamino or dialkylamino group, preferably a methyl or ethylamino ordimethyl or diethylamino group.

[0091] A preferred composition of formula (10) is4-F-Phe-3,4-Dehydro-Pro-Arg-Gly-Gly-Trp-NH₂ (SEQ NO: 80).

[0092] A group of preferred compositions of the hexapeptides of formula(10) which may be utilized alone or in combination with other peptidesdisclosed herein to treat patients suffering from physiological,psychosomatic, neurological or psychiatric disorders includeshexapeptides characterized by addition of a C-terminus amino acid ofTrp, optional modification of the heterocyclic nitrogen ring of Pro¹,preferably a cis- or trans-4-OH group, a fluorine atom at position 4 ofPhe. Preferably, the hexapeptides include Arg at AA²; Trp at AA³; andIle or Gly at AA⁴, and the C-terminus amide remains unmodified.Exemplary hexapeptides are represented by formula (10a):

R¹-Phe-R²-Pro¹-AA²-AA⁴-Gly-Trp-NH₂   (10a)

[0093] wherein R¹, R², AA², and AA⁴ are as defined above for formula(1). Preferred peptides of formula (10a) include 4-F-Phe-cis- ortrans-4-OH-Pro-Arg-Gly-Gly-Trp-NH₂ (SEQ ID NO: 58) and 4-F-Phe-cis- ortrans-4-OH-Pro-Arg-Ile-Gly-Trp-NH₂ (SEQ ID NO: 67).

[0094] Another embodiment of the invention provides heptapeptidecompositions or pharmaceutically acceptable salts thereof, includingaddition of both a N-terminus amino acid and a C-terminus amino acid canbe represented by the following formula (11):

R¹-AA¹-R²-Pro¹-AA²-AA⁴-AA⁵-Gly-AA³-R   (11)

[0095] where Pro¹ represents the amino acid Pro or dehydro-Pro; AA¹represents an amino acid of the group of Phe or Tyr; AA² represents anamino acid of the group of Leu, Ile, Arg, D-Arg, Trp, or canavanine; AA³represents the amino acid Trp; AA⁴ and AA⁵ represent the amino acid Glyor Ile; R represents a carboxyl group, hydroxyalkyl group, a carbamylgroup, an alkylcarbamyl group, or an alkoxycarbonyl group; and, R¹ andR² each independently represent a hydrogen atom, a lower alkyl group,preferably having 1 to 3 carbon atoms, a halogen atom, preferably afluorine or chlorine atom, a hydroxyl group, preferably a cis- ortrans-4-OH— group, a sulphydryl group, preferably a cis- ortrans-4-thio- group, or an alkylamino or dialkylamino group, preferablya methyl or ethylamino or dimethyl or diethylamino group, or a phosphonogroup (preferably as phosphono-tyrosine).

[0096] A preferred embodiment of a composition having formula (11) is4-F-Phe-cis- or trans-4-OH-Pro-Arg-Gly-Ile-Gly-Trp-NH₂ (SEQ ID NO: 56).

[0097] In another embodiment of the invention, tetrapeptide compositionsor pharmaceutically acceptable salts thereof including the addition ofan N-terminus amino acid of Phe to Arg; addition of a C-terminus aminoacid of Trp to Gly; and modification of the aromatic ring of Phe can berepresented by the following formula (12):

R¹-Phe-R²-Arg-Gly-Trp-NH₂   (12)

[0098] where R¹ represents a halogen atom and R² represents a carboxylicacid of a monocyclic organic compound with a three to six membered ringstructure having a hetero nitrogen atom. Preferred compositions of thepentapeptides of formula (12) include, but are not necessarily limitedto, 4-F-Phe-isonipecotic acid-Arg-Gly-Trp-NH₂(4-pyridinecarboxylic acid)(SEQ NO: 100), 4-F-Phe-2-Carboxy-Azetidine-Arg-Gly-Trp-NH₂ (SEQ NO:101), 4-F-Phe-2-carboxy-Aziridine-Arg-Gly-Trp-NH₂ (SEQ NO: 103),4-F-Phe-3-Carboxy-1,4,5,6-Tetrahydropyridine-Arg-Gly-Trp-NH₂ (SEQ NO:105), 4-F-Phe-2-Carboxypyrrole-Arg-Gly-Trp-NH₂ (SEQ NO: 106).

[0099] In another embodiment of the invention, pentapeptide compositionsor pharmaceutically acceptable salts thereof including replacement ofPro with Arg; addition of an N-terminus amino acid of Phe to Arg;addition of an internal amino acid; addition of a C-terminus amino acidof Trp to Gly; and modification of the aromatic ring of Phe can berepresented by the following formula (13):

R¹-Phe-AA¹-Arg-Gly-Trp-NH₂   (13)

[0100] where AA¹ represents an amino acid selected from the groupcomprising 1-amino-1-carboxycyclopentane and1-amino-1-carboxy-cyclopropyl and R¹ represents a halogen atom.Preferred compositions of the pentapeptides of formula (13) include4-F-Phe-1-Amino-1-Carboxycyclopentane-Arg-Gly-Trp-NH₂ (SEQ NO: 102) and4-F-Phe-1-Amino-1-Carboxy-Cyclopropyl-Arg-Gly-Trp-NH₂ (SEQ NO: 104).

[0101] In some embodiments, in peptide compositions represented by anyof formula (7), (8), (9), (10), or (11), Gly may be replaced by Val, Saror Ala. One preferred peptide composition wherein Gly is substitutedwith Sar in formula (7) is 4-F-Phe-3,4-Dehydro-Pro-Arg-Sar-Trp-NH₂ (SEQNO: 110).

[0102] Preferred compositions of the present invention are peptides thatshow higher activity in the Porsolt swim test than known compounds fortreating depression and/or anxiety, including SSRIs and MIF. Thepreferred peptides may vary in length, with particularly preferredpeptides being tetrapeptides, pentapeptides, hexapeptides andheptapeptides. Exemplary particularly preferred peptides may berepresented by the formula:

R¹-Phe-Pro¹-AA²-AA³-NH₂,

[0103] for a tetrapeptide, wherein R¹ is preferably a halogen atom, mostpreferably a fluorine or chlorine atom, a carboxyl group, an amino groupor a nitro group, with all modifications preferably at the C4 atom ofPhe; Pro¹ is 3,4-dehydro Pro, Homo-Pro, cis- or trans-4OH-Pro or Pro, aslisted in order of preference, AA² is preferably Ile, Leu or Arg; andAA³ is preferably Gly or Trp.

[0104] A highly preferred tetrapeptide is Pro-Ile-Gly-Trp (SEQ ID NO:3).

[0105] Preferred pentapeptides, hexapeptides and heptapeptides,according to the invention, are represented by the formula:

R¹-Phe-Pro¹-AA²-Gly-AA_((n))-AA³-NH₂,

[0106] wherein R¹ is preferably a halogen atom, preferably a fluorine orchlorine atom, a carboxyl group, an amino group or a nitro group, withall modifications preferably at the C4 atom of Phe; Pro¹ is 3,4-dehydroPro, Homo-Pro, cis- or trans-4OH-Pro or Pro, as listed in order ofpreference, AA² is preferably Arg, Ile, Leu or His, with Arg beingespecially preferred; AA_((n)) is 0-2 amino acid residues, if n=1, thenGly is preferred and if n=2, then Ile-Gly, Ile-Ile or Gly-Gly ispreferred; AA³ is preferably Trp or Gly, with Trp most preferred.

[0107] Also within the scope of the present invention are combinationsof any of the peptides of formula (1) through formula (11) and the useof such combinations in treating physiological, psychosomatic,neurological or psychiatric disorders in patients. Also included arechemically combined polypeptides formed by combining two or more of thepeptides disclosed herein. Such chemically combined polypeptidespreferably comprise from at least about three to at least about tenmodified and/or unmodified amino acids.

[0108] The present invention further provides admixtures of one or moreof the peptides of formula (1) through formula (11) with knownantidepressant compounds such as amitriptyline, fluoxetine (Prozac) andsertraline (Zoloft). It is within the ordinary skill of the artisan togenerate various admixtures with the peptides of the present inventionbeyond the exemplifications disclosed throughout this specification.

[0109] The peptides of the present invention are preferably formulatedin a suitable pharmaceutical carrier for in vivo administration to thepatient by any standard method known in the art such that apharmacologically effective concentration reaches the site of action.For the methods and compositions disclosed herein for treatingphysiological, psychosomatic, neurological, psychological or psychiatricdisorders, the preferred site of action is the brain. Exemplary routesof administration include oral (mouth or peroral administration),sublingual, parenteral (e.g., intravenous, intraspinal, intrathecal,intraventricular, epidermal, intracisternal, intracutaneous orintradermal, subcutaneous, or intramuscular), epicutaneous, transdermal,intranasal, vaginal, and rectal, as well as by inhalation in the formof, for example, a polydisperse or microdisperse aerosol.

[0110] The tripeptide hormone fragment having the general formulaPro-Leu-Gly-NH₂, otherwise known as L-prolyl L-leucyl glycine,melanocyte stimulating inhibitory factor, melanotrophic releaseinhibiting factor, or MIF, is known to exhibit antidepressant activity.MIF is typically reported in literature as having the tripeptidestructure Pro-Leu-Gly-NH₂ or Pro-Leu-Gly-amide. MIF is also referred toherein as Pro-Leu-Gly-NH₂.

[0111] It has been found that modifications of the tripeptide structureof MIF result in novel peptides useful in treating patients sufferingfrom physiological, psychosomatic, neurological, physiological orpsychiatric disorders, including PMS, chronic fatigue syndrome,fibromyalgia and seasonal affective disorder. Such modifications targetamino terminus residues, carboxyl terminus residues and internalresidues, including addition and substitution of amino acid residues andmodification of the peptide bonds and functional side groups ofrespective amino acid residues as more fully described hereinbelow.Peptides produced using such modifications, and the use of such peptidesin treating physiological, psychosomatic, neurological, physiological orpsychiatric disorders, are within the scope of the present invention,and may be administered according to the routes disclosed herein.

[0112] In general, peptides within the scope of the present inventioncan be made using known amino acids, such as for example, Ala, Arg,D-Arg, Gly, Ile, Leu, D-Leu, Lys, Orn, Phe, Pro, dehydro-Pro, Sar, Trp,and Tyr. Preferred peptides are made by additions or substitutions atthe amino terminus (N-terminus), carboxyl terminus (C-terminus) and/oradditions or substitutions of internal amino acid residues to thesequence Pro-Leu-Gly-NH₂. Carboxyl terminus modifications of thepeptides of the invention can include replacement of the carbamyl(amide) group at the carboxyl terminus of Pro-Leu-Gly-NH₂ by, forexample, a carboxyl (acid) group, a hydroxyalkyl (alcohol) group, analkoxycarbonyl (ester) group, or an alkylcarbamyl (alkylated amide)group. Amino terminus and internal modifications of the peptides of theinvention can include additions or eliminations on the heterocyclic,aromatic, and other carbon residues of the amino acids with an alkylgroup, preferably an alkyl group having 1 to 3 carbon atoms, a dehydro(anhydro) group, a halo group, a hydroxyl group, a sulphydryl group, analkylamino group, or a dialkylamino group. In some embodiments, theamino groups of the peptides of the invention can be alkylated,preferably with an alkyl group having 1 to 3 carbon atoms. Suchadditions, substitutions, eliminations, and/or modifications can becarried out by conventional polypeptide synthesis and organic chemistrysynthesis techniques known to those skilled in the art.

[0113] The groupings of the peptides of the invention into the formulasdescribed herein are provided only as a matter of convenience and shouldnot be considered limiting in any manner.

[0114] In one embodiment, the peptides are tripeptides characterizedeither by optional replacement of the Leu residue of Pro-Leu-Gly-NH₂with an amino acid selected from the group of Trp, Orn, Lys, Arg, D-Arg,or Ile; optional replacement of the Pro residue with dehydro-Pro,preferably 3,4-dehydro-Pro; optional modification of the carboxylterminus amide group with a substituent selected from a carboxyl group,an hydroxyalkyl group, preferably a hydroxymethyl group, analkoxycarbonyl group, or an alkylated carbamyl group; optionalmodification of the amino terminus heterocyclic group ordehydro-heterocyclic group with a substituent selected from the group ofa lower alkyl group, preferably having 1 to 3 carbon atoms, a halogenatom, preferably a fluorine or chlorine atom, a hydroxyl group,preferably a cis- or trans-4-OH— group, a sulphydryl group, preferably acis- or trans-4-thio- group; or an alkylamino group or a dialkylaminogroup, preferably a methyl or ethylamino or a dimethyl or diethylaminogroup; and/or optional modification of the hydrogen atoms at thenitrogen atoms of the amino acid peptide bonds with a lower alkyl group,preferably having 1 to 3 carbon atoms.

[0115] Tripeptides or pharmaceutically acceptable salts thereof can berepresented by formula (1):

R¹-Pro¹-AA¹-NR²-CH₂-R   (1)

[0116] where Pro¹ represents the amino acid Pro or dehydro-Pro,preferably 3,4-dehydro Pro; AA¹ represents an amino acid of the group ofTrp, Orn, Lys, Leu, Arg, D-Arg, or Ile; R represents a carboxyl group, ahydroxyalkyl group, a carbamyl group, an alkylcarbamyl group, or analkoxycarbonyl group; R¹ represents a hydrogen atom, a lower alkylgroup, preferably having 1 to 3 carbon atoms, a halogen atom, preferablya fluorine or chlorine atom, a hydroxyl group, sulphydryl group, or analkylamino or dialkylamino group, preferably a methyl or ethylaminogroup or dimethyl or diethylamino group; and, R² represents a hydrogenatom or a lower alkyl group, preferably having 1 to 3 carbon atoms, withthe proviso that where Pro¹ is Pro and AA¹ is Leu, then R¹ and R² arenot both hydrogen when R is a carbamyl (amide) group.

[0117] Some preferred tripeptides of formula (1) which may be utilizedalone or in combination with other peptides disclosed herein to treatpatients suffering from physiological, psychosomatic, neurological orpsychiatric disorders are characterized by replacement of Leu, and arefurther characterized by having the N-terminus Pro¹ residue andC-terminus amide group remain unmodified, which can be represented byformula (1a). Formula (1a) is depicted as:

Pro¹-AA¹-Gly-NH₂   (1a)

[0118] wherein Pro¹ and AA¹ are as described above for formula (1). Thetripeptides of formula (1a), may be utilized alone or in combinationwith other peptides disclosed herein to treat patients suffering fromphysiological, psychosomatic, neurological or psychiatric disorders.Preferred compositions of the tripeptides of formula (1a) are:

Pro-Trp-Gly-NH₂;

Pro-Arg-Gly-NH₂;

Pro-D-Arg-Gly-NH₂;

Pro-Lys-Gly-NH₂;

Pro-Orn-Gly-NH₂;

[0119] and,

Pro-Ile-Gly-NH₂.

[0120] A second group of preferred compositions of the tripeptides offormula (1) which may be utilized alone or in combination with otherpeptides disclosed herein to treat patients suffering fromphysiological, psychosomatic, neurological or psychiatric disorders arecharacterized by optional replacement of Leu, and are furthercharacterized by optional modification of the N-terminus heterocyclicnitrogen ring of Pro¹, preferably at the C-4 position of theheterocyclic nitrogen ring, and particularly preferably by addition of acis- or trans-hydroxyl group or a cis- or trans-sulphydryl group at theC4 position, and wherein the C-terminus amide group preferably remainsunmodified, which can be represented by formula (1b):

R¹-Pro¹-AA¹-Gly-NH₂   (1b)

[0121] wherein Pro¹, AA¹ and R¹ are as described above for formula (1).Preferred compositions of the tripeptides of formula (1b) are:

cis- or trans-4-OH-Pro-D-Arg-Gly-NH₂;

cis- or trans-4-OH-Pro-Ile-Gly-NH₂;

cis- or trans-4-OH-Pro-Arg-Gly-NH₂;

cis- or trans-4-OH-Pro-Trp-Gly-NH₂;

[0122] and,

cis- or trans-4-thio-Pro-Leu-Gly-NH₂.

[0123] A third group of preferred compositions of the tripeptides offormula (1) which may be utilized alone or in combination with otherpeptides disclosed herein to treat patients suffering fromphysiological, psychosomatic, neurological or psychiatric disorders arecharacterized by optional replacement of Leu, optional modification ofthe C-terminus amide group, optional modification of the C-terminushydrogen atom at the nitrogen comprising the peptide bond betweenLeu-Gly, and by having the N-terminus heterocyclic nitrogen ring of Pro¹remain unmodified, which can be represented by formula (1c). Formula(1c) is depicted as:

Pro¹-AA¹-NR²—CH₂—R   (1c)

[0124] wherein Pro¹, AA¹, and R and R² are as described above forformula (1), with the proviso that where Pro¹ is Pro and AA¹ is Leu, R²cannot be hydrogen when R is either a carboxyl group or a hydroxyalkylgroup, and with the further proviso that when Pro¹ is Pro and AA¹ isTrp, R² is not hydrogen when R is a hydroxyalkyl group. Preferredcompositions of the tripeptides of formula (1c) are:

Pro-Leu-N(CH₃)CH₂₋CONH₂;

[0125] and,

Pro-Trp-NHCH₂—CO₂H.

[0126] In another embodiment of the invention, additional tripeptidesare characterized by replacement of Leu with Arg or D-Arg; replacementof Gly with Ala; optional replacement of Pro with dehydro-Pro,preferably 3,4-dehydro-Pro; optional modification of the C-terminusamide group with a functional group selected from a carboxyl group, ahydroxyalkyl group, preferably a hydroxymethyl group, an alkoxycarbonylgroup, and an alkylated carbamyl group; optional modification of theN-terminus heterocyclic nitrogen ring of Pro¹ with a substituentselected from a lower alkyl group preferably having 1 to 3 carbon atoms,a halogen atom, preferably a fluorine or chlorine atom, a hydroxylgroup, preferably a cis- or trans-4-OH— group, a sulphydryl group,preferably a cis- or trans-4-thio- group; and an alkylamino group or adialkylamino group, preferably a methyl or ethyl amino or dimethyl ordiethyl amino group; and/or optional modification of the hydrogen atomsat the nitrogen atoms of the amino acid peptide bonds with a lower alkylgroup, preferably having 1 to 3 carbon atoms. This embodiment includespeptides represented by the following formula (2):

R¹-Pro¹-AA¹-Ala-R   (2)

[0127] and pharmaceutically acceptable salts thereof, where Pro¹represents the amino acid Pro or dehydro-Pro, preferably 3,4-dehydroPro; AA¹ represents an amino acid of the group of Arg or D-Arg; Rrepresents a carboxyl group, a hydroxyalkyl group, a carbamyl group, analkylcarbamyl group, or an alkoxycarbonyl; and, R¹ represents a hydrogenatom, a lower alkyl group, preferably having 1 to 3 carbon atoms, ahalogen atom, preferably a fluorine or chlorine atom, a hydroxyl group,a sulphydryl group, or an alkylamino or dialkylamino group, preferably amethyl or ethylamino or dimethyl or diethylamino group.

[0128] Exemplary preferred tripeptides of formula (2) which may beutilized alone or in combination with other peptides disclosed herein totreat patients suffering from physiological, psychosomatic, neurologicalor psychiatric disorders are characterized by replacement of the Leu andGly in Pro-Leu-Gly-NH₂, and by the N-terminus Pro¹ residue andC-terminus amide remain unmodified, which can be represented by formula(2a). Formula (2a) is depicted as:

Pro¹-AA¹-Ala-NH₂   (2a)

[0129] wherein Pro¹ and AA¹ are as described above for formula (2).Preferred tripeptides of formula (2a) are:

Pro-Arg-Ala-NH₂;

[0130] and,

Pro-D-Arg-Ala-NH₂.

[0131] In further embodiments, the small tripeptides are characterizedby replacement of Leu with Orn; replacement of Gly with Tyr; optionalreplacement of Pro with dehydro-Pro, preferably 3,4-dehydro-Pro;optional modification of the C-terminus amide group with a substituentselected from the group of a carboxyl group, a hydroxyalkyl group,preferably hydroxymethyl, an alkoxycarbonyl group, or an alkylatedcarbamyl group; optional modification of the N-terminus heterocyclicnitrogen ring of Pro¹ with a substituent selected from lower alkylgroups, preferably having 1 to 3 carbon atoms, a halogen atom,preferably a fluorine or chlorine atom, a hydroxyl group, preferably acis- or trans-4-OH— group, a sulphydryl group, preferably a cis- ortrans-4-thio- group, or an alkylamino group or a dialkylamino group,preferably a methyl or ethylamino or a dimethyl or diethylamino group;and/or optional modification of the hydrogen atoms at the nitrogen atomsof the amino acid peptide bonds with a lower alkyl group, preferablyhaving 1 to 3 carbon atoms. Such tripeptides or pharmaceuticallyacceptable salts thereof can be represented by formula (3):

R¹-Pro¹-AA¹-Tyr-R   (3)

[0132] where Pro¹ represents the amino acid Pro or dehydro-Pro,preferably 3,4-dehydro Pro; AA¹ represents the amino acid Orn; Rrepresents a carboxyl group, a hydroxyalkyl group, a carbamyl group, analkylcarbamyl group, or an alkoxycarbonyl group; and, R¹ represents ahydrogen atom, a lower alkyl group, preferably having 1 to 3 carbonatoms, a halogen atom, preferably a fluorine or chlorine atom, ahydroxyl group, preferably a cis- or trans-4-OH— group, a sulphydrylgroup, preferably a cis- or trans-4-thio- group, or an alkylamino ordialkylamino group, preferably a methyl or ethylamino or a dimethyl ordiethylamino group.

[0133] The following paragraphs disclose compositions of the tripeptidesof formula (3), which may be utilized alone or in combination with otherpeptides disclosed herein to treat patients suffering fromphysiological, psychosomatic, neurological or psychiatric disorders.

[0134] Tripeptides of formula (3) that may be utilized alone or incombination with other peptides disclosed herein to treat patientssuffering from physiological, psychosomatic, neurological or psychiatricdisorders, and that are characterized by replacement of Leu and Gly,optional modification of the N-terminus heterocyclic nitrogen ring ofPro¹, and by having the C-terminus amide remain unmodified, can berepresented by formula (3a):

R¹-Pro¹-AA¹-Tyr-NH₂   (3a)

[0135] where Pro¹, AA¹ and R¹ are as described for formula (3).Preferred tripeptides of formula (3a) are:

Pro-Orn-Tyr-NH₂;

[0136] and

cis- or trans-4-OH-Pro-Orn-Tyr-NH₂.

[0137] In yet another embodiment, the peptides are tetrapeptidescharacterized by either addition of a C-terminus amino acid of Trp orTyr to Gly or addition of a N-terminus amino acid of Trp or Phe to Proto Pro-Leu-Gly-NH₂; optional replacement of Leu with Ile, Arg, D-Arg, orTrp; optional replacement of Pro with dehydro-Pro, preferably3,4-dehydro-Pro; optional modification of the C-terminus amide with asubstituent selected from the group of a carboxyl group, a hydroxyalkylgroup, preferably a hydroxymethyl group, an alkoxycarbonyl group, or analkylated carbamyl group; optional modification of the heterocyclicnitrogen rings of Pro¹ and Trp and optional modification of the aromaticring of Phe with a substituent selected from the group of a lower alkylgroup, preferably having 1 to 3 carbon atoms, a halogen atom, preferablya fluorine or chlorine atom, a hydroxyl group, preferably a cis- ortrans-4-OH— group, a sulphydryl group, preferably a cis- ortrans-4-thio- group, or an alkylamino or a dialkylamino group,preferably a methyl or ethylamino or a dimethyl or diethylamino group;and/or optional modification of the hydrogen atoms at the nitrogen atomsof the amino acid peptide bonds with a lower alkyl group, preferablyhaving 1 to 3 carbon atoms.

[0138] One embodiment of the tetrapeptides or pharmaceuticallyacceptable salts thereof including a C-terminus amino acid addition canbe represented by the following formula (4):

R¹-Pro¹-AA¹-Gly-AA²-R   (4)

[0139] where Pro¹ represents the amino acid Pro or dehydro-Pro,preferably 3,4-dehydro Pro; AA¹ represents an amino acid of the group ofIle, Leu, Arg, D-Arg or Trp; AA² represents Trp or Tyr; R represents acarboxyl group, hydroxyalkyl group, a carbamyl group, an alkylcarbamylgroup, or an alkoxycarbonyl group; and, R¹ represents a hydrogen atom, alower alkyl group, preferably having 1 to 3 carbon atoms, a dehydrogroup, a halogen atom, preferably a fluorine or chlorine atom, ahydroxyl group, a sulphydryl group, or an alkylamino or dialkylaminogroup, preferably a methyl or ethylamino or dimethyl or diethylaminogroup.

[0140] Preferred tetrapeptides of formula (4) that may be utilized aloneor in combination with other peptides disclosed herein to treat patientssuffering from physiological, psychosomatic, neurological or psychiatricdisorders are characterized by addition of Trp or Tyr to the C-terminusGly, by optional replacement of Leu, by optional modification of theN-terminus heterocyclic nitrogen ring of Pro¹, and by having theC-terminus amide remain unmodified, which can be represented by formula(4a):

R¹-Pro-AA¹-Gly-AA²-NH₂   (4a)

[0141] wherein Pro¹, AA¹, AA², and R¹ are as described for formula (4).Preferred tetrapeptides of formula (4a) are: (SEQ ID NO:1) cis- ortrans-4-OH-Pro-Leu-Gly-Trp-NH₂; (SEQ ID NO:2) cis- ortrans-4-OH-Pro-Ile-Gly-Trp-NH₂; cis- ortrans-4-OH-Pro-D-Arg-Gly-Trp-NH₂; and,3,4-dehydro-Pro-D-Arg-Gly-Trp-NH₂.

[0142] Another preferred tetrapeptide of formula (4a) is

3,4-dehydro-Pro-Arg-Gly-Trp-NH₂ (SEQ ID NO: 62).

[0143] Alternative preferred tetrapeptides of formula (4) that may beutilized alone or in combination with other peptides disclosed herein totreat patients suffering from physiological, psychosomatic, neurologicalor psychiatric disorders are characterized by addition of Trp or Tyr tothe C-terminus Gly, by optional replacement of Leu, and by having theN-terminus heterocyclic nitrogen ring of Pro¹ remain unmodified, whichcan be represented by formula (4b):

Pro¹-AA¹-Gly-AA²-NH₂   (4b)

[0144] wherein Pro¹, AA¹ and AA² are as described for formula (4).Preferred compositions of the tetrapeptides of formula (4b) are:Pro-Ile-Gly-Trp-NH₂; (SEQ ID NO:3) 3,4-dehydro-Pro-Ile-Gly-Trp-NH₂; (SEQID NO:4) Pro-Leu-Gly-Trp-NH₂; (SEQ ID NO:5) Pro-Leu-Gly-Tyr-NH₂; (SEQ IDNO:6) Pro-Arg-Gly-Trp-NH₂; (SEQ ID NO:7) Pro-Trp-Gly-Trp-NH₂; (SEQ IDNO:8) Pro-D-Arg-Gly-Trp-NH₂; and, Pro-Ile-Gly-Tyr-NH₂. (SEQ ID NO:9)

[0145] Another embodiment of the tetrapeptide compositions orpharmaceutically acceptable salt thereof including a N-terminus aminoacid addition can be represented by formula (5):

R¹-AA¹-R²-Pro¹-AA²-Gly-R   (5)

[0146] where Pro¹ represents the amino acid Pro or dehydro-Pro,preferably 3,4-dehydro Pro; AA¹ represents an amino acid of the group ofTrp, Tyr, or Phe; AA² represents an amino acid of the group of Leu, Ile,or Trp; R represents a carboxyl group, hydroxyalkyl group, a carbamylgroup, an alkylcarbamyl group, or an alkoxycarbonyl group; and, R¹ andR² each independently represent a hydrogen atom, a lower alkyl group,preferably having 1 to 3 carbon atoms, a halogen atom, preferably afluorine or chlorine atom, a hydroxyl group, a sulphydryl group, or analkylamino or dialkylamino group, preferably a methyl or ethylamino ordimethyl or diethylamino group.

[0147] In some preferred embodiments, tetrapeptides of formula (5) areused in combination with one or more other peptides disclosed herein.

[0148] Exemplary tetrapeptides of formula (5) that may be utilized aloneor in combination with other peptides disclosed herein to treat patientssuffering from physiological, psychosomatic, neurological or psychiatricdisorders are characterized by addition of Trp, Tyr, or Phe to theN-terminus Pro¹, optional replacement of Leu, optional modification ofthe heterocyclic nitrogen rings of Pro¹ and Trp and optionalmodification of the aromatic ring of Phe and Tyr, and wherein theC-terminus amide remains unmodified, which can be represented by formula(5a):

R¹-AA¹-R²-Pro¹-AA²-Gly-NH₂   (5a)

[0149] wherein Pro¹, AA¹, AA², R¹, and R² are as described for formula(5), with the proviso that where Pro¹ is Pro, R¹ and R² cannot both be ahydrogen atom when AA¹ is Tyr and AA² is Trp, since Tyr-Pro-Trp-Gly-NH₂is a known compound, and with the further proviso that where Pro¹ is Proand AA² is Leu, R¹ and R² cannot both be a hydrogen atom when AA¹ is Pheor Tyr. Preferred compositions of the tetrapeptides of formula (5a) are:(SEQ ID NO:10) Trp-Pro-Leu-Gly-NH₂; (SEQ ID NO:11) Phe-Pro-Leu-Gly-NH₂;(SEQ ID NO:12) 4-F-Phe-Pro-Leu-Gly-NH₂; (SEQ ID NO:13)4-Cl-Phe-Pro-Leu-Gly-NH₂; (SEQ ID NO:14) 4-F-Phe-Pro-Ile-Gly-NH₂; (SEQID NO:15) 4-F-Phe-cis- or trans-4-OH-Pro-Leu-Gly-NH₂; (SEQ ID NO:16)4-F-Phe-cis- or trans-4-OH-Pro-Ile-Gly-NH₂; (SEQ ID NO:17)Trp-Pro-Leu-Gly-NH₂; (SEQ ID NO:18) Trp-Pro-Ile-Gly-NH₂; (SEQ ID NO:19)Trp-cis- or trans-4-OH-Pro-Leu-Gly-NH₂; (SEQ ID NO:20) Trp-cis- ortrans-4-OH-Pro-Ile-Gly-NH₂

[0150] An additional preferred tetrapeptide of formula (5a) is

4-Cl-Phe-cis- or trans-4-OH-Pro-Ile-Gly-NH₂ (SEQ ID NO: 60).

[0151] Another group of preferred tetrapeptides of formula (5) that maybe utilized alone or in combination with other peptides disclosed hereinto treat patients suffering from physiological, psychosomatic,neurological or psychiatric disorders are characterized by addition ofPhe to the N-terminus Pro¹, optional replacement of Leu with Arg,optional modification of the heterocyclic nitrogen ring of Pro¹ andoptional modification of the aromatic ring of Phe, and modification ofthe C-terminus amide to a carbamyl group, which can be represented byformula (5b):

R¹-AA¹-R²-Pro¹-AA²-Gly-R   (5b)

[0152] wherein Pro¹, AA¹, AA², R¹, R² and R are as described for formula(5). Preferred compositions of the tetrapeptides of formula (5b)include, but are not solely limited to, additional optional modificationof the N-terminus heterocyclic nitrogen ring of Pro¹ with a cis- ortrans-4-OH— group; and additional optional modifications at AA²,preferably Arg. A preferred peptide of formula (5b) is 4-F-Phe-cis- ortrans-4-OH-Pro-Arg-Gly-1,2,3,4-Tetrahydroisoquinoline-3-carboxamide (SEQNO: 75).

[0153] In yet another embodiment of the invention, the peptides arepentapeptides with either addition of two N-terminus amino acids of Phe,Tyr, Leu, or Ile to Pro¹, addition of a N-terminus amino acid of Phe orTyr to Pro¹ and a C-terminus amino acid addition of Trp to Gly, oraddition of a C-terminus amino acids of Trp to Gly and an internal aminoacid between Pro¹ and Gly, to Pro-Leu-Gly-NH₂; optional replacement ofLeu with Ile or Trp; optional replacement of Pro with dehydro-Pro,preferably 3,4-dehydro-Pro; optional modification of the C-terminusamide with a substituent selected from the group of a carboxyl group, ahydroxyalkyl group, preferably a hydroxymethyl group, an alkoxycarbonylgroup, or an alkylated carbamyl group; optional modification of theheterocyclic nitrogen ring of Pro¹ and optional modification of thearomatic rings of Tyr or Phe with a substituent selected from the groupof a lower alkyl group, preferably having 1 to 3 carbon atoms, a halogenatom, preferably a fluorine or chlorine atom, a hydroxyl group,preferably a cis- or trans-4-OH— group, a sulphydryl group, preferably acis- or trans-4-thio- group, or an alkylamino or a dialkylamino group,preferably a methyl or ethylamino or a dimethyl or diethylamino group;and/or optional modification of the hydrogen atoms at the nitrogen atomsof the amino acid peptide bonds with a lower alkyl group, preferablyhaving 1 to 3 carbon atoms.

[0154] One embodiment of the pentapeptide compositions includingaddition of two N-terminus amino acids or pharmaceutically acceptablesalt thereof can be represented by formula (6):

R¹-AA¹-AA²-R²-Pro¹-AA³-Gly-R   (6)

[0155] where Pro¹ represents the amino acid Pro or dehydro-Pro,preferably 3,4-dehydro Pro; AA¹ and AA² each independently represent anamino acid of the group of Phe or Tyr; AA³ represents an amino acid ofthe group of Leu or Ile; R represents a carboxyl group, hydroxyalkylgroup, a carbamyl group, an alkylcarbamyl group, or an alkoxycarbonylgroup; and, R¹ and R² each independently represent a hydrogen atom, alower alkyl group, preferably having 1 to 3 carbon atoms, a halogenatom, preferably a fluorine or chlorine atom, a hydroxyl group,preferably a cis- or trans-4-OH— group, a sulphydryl group, preferably acis- or trans-4-thio- group, or an alkylamino or dialkylamino group,preferably a methyl or ethylamino or dimethyl or diethylamino group.

[0156] Preferred pentapeptides of formula (6) that may be utilized aloneor in combination with other peptides disclosed herein to treat patientssuffering from physiological, psychosomatic, neurological or psychiatricdisorders are characterized by addition of two N-terminus amino acids ofPhe and Tyr to Pro¹, optional modification of the heterocyclic nitrogenring of Pro¹ and optional modification of the aromatic rings of Phe orTyr, optional replacement of Leu, and by having the C-terminus amide ofGly remain unmodified, which can be represented by formula (6a):

R¹-AA¹-AA²-R²-Pro¹-AA³-Gly-NH₂   (6a)

[0157] wherein Pro¹, AA¹, AA², R¹, and R² are as described for formula(6). Preferred pentapeptides of formula (6a) are: (SEQ ID NO:21)4-F-Phe-Tyr-Pro-Leu-Gly-NH₂; (SEQ ID NO:22)4-Cl-Phe-Tyr-Pro-Leu-Gly-NH₂; (SEQ ID NO:23) Phe-Tyr-Pro-Leu-Gly-NH₂;(SEQ ID NO:24) Phe-Tyr-Pro-Ile-Gly-NH₂; (SEQ ID NO:25) Phe-Tyr-cis- ortrans-4-OH-Pro-Leu-Gly-NH₂; (SEQ ID NO:26) Phe-Tyr-cis- ortrans-4-OH-Pro-Ile-Gly-NH₂; (SEQ ID NO:27) Tyr-Tyr-Pro-Leu-Gly-NH₂; (SEQID NO:28) Tyr-Tyr-Pro-Ile-Gly-NH₂; (SEQ ID NO:29) Tyr-Tyr-cis- ortrans-4-OH-Pro-Leu-Gly-NH₂; and, (SEQ ID NO:30) Tyr-Tyr-cis- ortrans-4-OH-Pro-Ile-Gly-NH₂.

[0158] Another embodiment of the invention provides pentapeptidecompositions or pharmaceutically acceptable salts thereof includingaddition of both a N-terminus amino acid and a C-terminus amino acidrepresented by formula (7):

R¹-AA¹-R²-Pro¹-AA²-Gly-AA³-R   (7)

[0159] where Pro¹ represents the amino acid Pro or dehydro-Pro,preferably 3,4-dehydro Pro; AA¹ represents an amino acid of the group ofPhe or Tyr; AA² represents an amino acid of the group of Leu, Ile, Arg,D-Arg, or Trp; AA³ represents the amino acid Trp; R represents acarboxyl group, hydroxyalkyl group, a carbamyl group, an alkylcarbamylgroup, or an alkoxycarbonyl group; and, R¹ and R² each independentlyrepresent a hydrogen atom, a lower alkyl group, preferably having 1 to 3carbon atoms, a halogen atom, preferably a fluorine or chlorine atom, ahydroxyl group, preferably a cis- or trans-4-OH— group, a sulphydrylgroup, preferably a cis- or trans-4-thio- group, or an alkylamino ordialkylamino group, preferably a methyl or ethylamino or dimethyl ordiethylamino group.

[0160] Preferred pentapeptides of formula (7) which may be utilizedalone or in combination with other peptides disclosed herein to treatpatients suffering from physiological, psychosomatic, neurological orpsychiatric disorders are characterized by addition of a N-terminusamino acid of Phe or Tyr to Pro¹, addition of a C-terminus amino acid ofTrp to Gly, optional modification of the heterocyclic nitrogen ring ofPro¹ and optional modification of the aromatic rings of Phe or Tyr,optional replacement of Leu with Ile, Arg, D-Arg, or Trp, and theC-terminus amide remaining unmodified, and can be represented by formula(7a):

R¹-AA¹-R²-Pro¹-AA²-Gly-Trp-NH₂   (7a)

[0161] wherein Pro¹, AA¹, AA², R¹, and R² are as described for formula(7). Preferred pentapeptides of formula (7a) are: (SEQ ID NO:31)Phe-Pro-Leu-Gly-Trp-NH₂; (SEQ ID NO:32) Tyr-Pro-Leu-Gly-Trp-NH₂; (SEQ IDNO:33) Phe-cis- or trans-4-OH-Pro-Leu-Gly-Trp-NH₂; (SEQ ID NO:34)Phe-Pro-Ile-Gly-Trp-NH₂; (SEQ ID NO:35) Phe-cis- ortrans-4-OH-Pro-Ile-Gly-Trp-NH₂; (SEQ ID NO:36) Tyr-cis- ortrans-4-OH-Pro-Leu-Gly-Trp-NH₂; (SEQ ID NO:37) Tyr-Pro-Ile-Gly-Trp-NH₂;(SEQ ID NO:38) Tyr-cis- or trans-4-OH-Pro-Leu-Gly-Trp-NH₂; (SEQ IDNO:39) Tyr-Pro-Trp-Gly-Trp-NH₂; (SEQ ID NO:40) Tyr-cis- ortrans-4-OH-Pro-Trp-Gly-Trp-NH₂; (SEQ ID NO:41) 4-F-Phe-cis- ortrans-4-OH-Pro-Ile-Gly-Trp-NH₂; (SEQ ID NO:42) 4-F-Phe-cis- ortrans-4-OH-Pro-Leu-Gly-Trp-NH₂; (SEQ ID NO:43) 4-F-Phe-cis- ortrans-4-OH-Pro-Arg-Gly-Trp-NH₂; and, 4-F-Phe-cis- ortrans-4-OH-Pro-D-Arg-Gly-Trp-NH₂.

[0162] Additional preferred pentapeptides of formula (7a) include: (SEQID NO:66) 3-F-Phe-cis- or trans-4-OH-Pro-Arg-Gly-Trp-NH₂; (SEQ ID NO:68)2-F-Phe-cis- or trans-4-OH-Pro-Arg-Gly-Trp-NH₂; and (SEQ ID NO:61)4-Cl-Phe-cis- or trans-4-OH-Pro-Arg-Gly-Trp-NH₂.

[0163] An additional group of preferred pentapeptides of formula (7a) ischaracterized by the optional modification of Pro¹ to dehydro-Pro,preferably 3,4-dehydro-Pro, and includes: (SEQ ID NO:72)4-F-Phe-3,4-dehydro-Pro-Ile-Gly-Trp-NH₂; and (SEQ ID NO:55)4-F-Phe-3,4-dehydro-Pro-Arg-Gly-Trp-NH₂.

[0164] Further embodiments encompassed within formula (7a) includecompounds having additional optional modifications at AA², preferablyArg, His, Homo-Arg, L-Allo-Ile, or canavanine; additional optionalmodifications at R¹ and/or R² (preferably R¹) and preferably an aminogroup, a carboxyl group, a nitro group, or a phosphono group (preferablyas phosphono-Tyr); additional optional modification of the heterocyclicnitrogen ring of Pro¹, preferably cis- or trans-4-OH or Homo-Pro.Additional preferred peptides of formula (7a) are: 4-NH₂-Phe-cis- ortrans-4-OH-Pro-Arg-Gly-Trp-NH₂; (SEQ ID NO:63) 4-F-Phe-cis- ortrans-4-OH-Pro-His-Gly-Trp-NH₂; (SEQ ID NO:64) 4-NO₂-Phe-cis- ortrans-4-OH-Pro-Arg-Gly-Trp-NH₂; (SEQ ID NO:65) 4-CH₃O-Phe-cis- ortrans-4-OH-Pro-Arg-Gly-Trp-NH₂; (SEQ ID NO:59) 4-F-Phe-cis- ortrans-4-OH-Pro-Homo-Arg-Gly-Trp-NH₂; (SEQ ID NO:71)4-F-Phe-Homo-Pro-Ile-Gly-Trp-NH₂; (SEQ ID NO:69)4-F-Phe-Homo-Pro-Arg-Gly-Trp-NH₂; and, (SEQ ID NO:57) 4-F-Phe-cis- ortrans-4-OH-Pro-L-Allo-Ile-Gly-Trp-NH₂. (SEQ ID NO:73)

[0165] Preferred pentapeptides of formula (7) which may be utilizedalone or in combination with other peptides disclosed herein to treatpatients suffering from physiological, psychosomatic, neurological orpsychiatric disorders are characterized by addition of an N-terminusamino acid of Phe; addition of a C-terminus amino acid of Trp to Gly;optional modification of the heterocyclic nitrogen ring of Pro¹ andoptional modification of the aromatic ring of Phe; and by the C-terminusamide remaining unmodified, and can be represented by formula (7b):

R¹-AA¹-R²-Pro¹-AA²-Gly-Trp-NH₂   (7b)

[0166] wherein AA¹ is Phe; and Pro¹, AA², R¹ and R² are as described forformula (7) with the following additional optional modification of theN-terminus heterocyclic nitrogen ring of Pro¹ with a substituentselected from the group consisting of cis-4-OH—, trans-4-OH—, cis-3-OH—,and trans-3-OH—; and additional optional modifications at R¹, preferablytwo or more halogen atoms or a cyano group. Preferred pentapeptides offormula (7b) include: 3,4-Dichloro-Phe-cis- ortrans-4-OH-Pro-Arg-Gly-Trp-NH₂; (SEQ NO:76) 4-NC-Phe-cis- ortrans-4-OH-Pro-Arg-Gly-Trp-NH₂; (SEQ NO:77) 4-F-Phe-cis- ortrans-4-OH-Pro-D-Leu-Gly-Trp-NH₂; and, (SEQ NO:78)4-F-Phe-trans-3-Hydroxy-Pro-Arg-Gly-Trp-NH₂. (SEQ NO:79)

[0167] Additional preferred pentapeptides of formula (7) that may beutilized alone or in combination with other peptides disclosed herein totreat patients suffering from physiological, psychosomatic, neurologicalor psychiatric disorders are characterized by addition of an N-terminusamino acid of Phe, addition of a C-terminus amino acid of Trp to Gly,optional modification of the heterocyclic nitrogen ring of Pro¹ andoptional modification of the aromatic ring of Phe, and the absence ofthe C-terminus amide, which can be represented by formula (7c):

R¹-AA¹-R²-Pro¹-AA²-Gly-Trp   (7c)

[0168] where Pro¹, AA¹, AA², R¹ and R² are as described for formula (7)with additional optional modifications at AA², preferably Homo-Arg; andadditional optional modification of the N-terminus heterocyclic nitrogenring of Pro¹ with a substituent selected from the group consisting ofcis-4-OH—, trans-4-OH—, cis-3-OH— and trans-3-OH. A preferred peptide offormula (7c) is 4-F-Phe-cis- or trans-4-OH-Pro-Homo-Arg-Gly-Trp (SEQ NO:74).

[0169] Another group of preferred pentapeptides of formula (7) that maybe utilized alone or in combination with other peptides disclosed hereinto treat patients suffering from physiological, psychosomatic,neurological or psychiatric disorders are characterized by addition ofan N-terminus amino acid of Phe, Tyr or PhenylGly; addition of aC-terminus amino acid of Trp or AzaTrp to Gly; optional modification ofthe N-terminus heterocyclic nitrogen ring of Pro¹ and optionalmodification of the aromatic rings of Phe, Tyr and PhenylGly; andadditional optional modification at R, preferably a hydroxyamino group,which can be represented by formula (7d):

R¹-AA¹-R²-Pro¹-AA²-Gly-AA³-R   (7d)

[0170] wherein Pro¹, AA¹, AA², AA³, R¹, R² and R are as described forformula (7) with the following additional optional modifications atPro¹, preferably Homo-Pro; additional optional modifications at AA¹,preferably PhenylGly; additional optional modifications at AA³,preferably AzaTrp; additional optional modifications at R¹, preferablytwo or more halogen atoms, a haloform, or a methoxyl group; additionaloptional modifications at R², preferably a cis- or trans-3-OH— group;and additional optional modifications at R, preferably a hydroxyaminogroup. Preferred pentapeptides of formula (7d) include: (SEQ NO:81)4-CH₃O-Phe-3,4-Dehydro-Pro-Arg-Gly-Trp-NH₂; (SEQ NO:82)2,4-Di-F-Phe-3,4-Dihydro-Pro-Arg-Gly-Trp-NH₂; (SEQ NO:83)4-CF₃-Phe-3,4-Dehydro-Pro-Arg-Gly-Trp-NH₂; (SEQ NO:84)4-F-PhenylGly-3,4-Dehydro-Pro-Arg-Gly-Trp-NH₂; (SEQ NO:85)3-F-Tyr-3,4-Dehydro-Pro-Arg-Gly-Trp-NH₂; (SEQ NO:86)4-F-Phe-3,4-Dehydro-Pro-Arg-Gly-Trp-NHOH; (SEQ NO:87)3,4-Di-Cl-Phe-3,4-Dihydro-Pro-Arg-Gly-Trp-NH₂; (SEQ NO:88)2-F-Tyr-3,4-Dehydro-Pro-Arg-Gly-Trp-NH₂; and, (SEQ NO:89)4-F-Phe-3,4-Dehydro-Pro-Arg-Gly-7-AzaTrp-NH₂.

[0171] Another group of preferred pentapeptides of formula (7) which maybe utilized alone or in combination with other peptides disclosed hereinto treat patients suffering from physiological, psychosomatic,neurological or psychiatric disorders are characterized by addition ofan N-terminus amino acid of Phe; addition of a C-terminus amino acid ofTrp to Gly; optional modification of the heterocyclic nitrogen ring ofPro¹ and optional modification of the aromatic rings of Phe and Trp; andby having the C-terminus amide remain unmodified, which can berepresented by formula (7e):

R¹-AA¹-R²-Pro¹-AA²-Gly-R⁴-Trp-NH₂   (7e)

[0172] wherein Pro¹, AA¹, AA², R¹ and R² are as described for formula(7) with the following additional optional modification of theN-terminus heterocyclic nitrogen ring of Pro¹ with a substituentselected from the group consisting of cis-4-OH—, trans-4-OH—, cis-3-OH—,and trans-3-OH—; and R⁴ represents a modification of the tryptophanresidue at one of C4, C5, C6 and C7 with a halogen atom, a hydroxylgroup, or an alkyl group. Preferred pentapeptides of formula (7e)include:

4-F-Phe-cis- or trans-4-OH-Pro-Arg-Gly-4-F-Trp-NH₂ (SEQ NO: 107); and,

4-F-Phe-cis- or trans-4-OH-Pro-Arg-Gly-7-Methyl-Trp-NH₂ (SEQ NO: 108).

[0173] Another group of preferred compositions of the pentapeptides offormula (7) which may be utilized alone or in combination with otherpeptides disclosed herein to treat patients suffering fromphysiological, psychosomatic, neurological or psychiatric disorders arecharacterized by addition of an N-terminus amino acid of Phe; additionof a C-terminus amino acid of Trp to Gly; optional modification of theheterocyclic nitrogen ring of Pro¹ and optional modification of thearomatic rings of Phe and Leu; and by having the C-terminus amide remainunmodified, which can be represented by formula (7f):

R¹-AA¹-R²-Pro¹-R⁵-AA²-Gly-Trp-NH₂   (7f)

[0174] wherein Pro¹, AA¹, AA², R¹ and R² are as described for formula(7) with the following additional optional modification of theN-terminus heterocyclic nitrogen ring of Pro¹ with a substituentselected from the group consisting of cis-4-OH—, trans-4-OH—, cis-3-OH—,and trans-3-OH—; and R⁵ represents at least one halogen atom. Apreferred composition of the pentapeptides of formula (7f) is4-F-Phe-4-OH-Pro-5,5,5-Trifluoro-Leu-Gly-Trp-NH₂ (SEQ NO: 109).

[0175] Another group of preferred pentapeptides of formula (7) which maybe utilized alone or in combination with other peptides disclosed hereinto treat patients suffering from physiological, psychosomatic,neurological or psychiatric disorders are characterized by addition ofan N-terminus amino acid of Phe; addition of a C-terminus amino acid ofTrp to Gly; additional optional modifications at Pro¹, preferablyHomo-Pro; optional modification of the heterocyclic nitrogen ring ofPro¹ and optional modification of the aromatic rings of Phe and Trp; andby having the C-terminus amide remain unmodified, which can berepresented by formula (7g):

R¹-AA¹-R²-Pro¹-AA²-Gly-R⁴-AA³-R   (7g)

[0176] wherein Pro¹, AA¹, AA², AA³, R¹, R² and R are as described forformula (7) with the following additional optional modifications atPro¹, preferably Homo-Pro or 3,4-dihydro-Pro; additional optionalmodifications at R², preferably cis- or trans-3-OH— group; and R⁴represents a halogen atom, a methyl group, a methoxyl group or ahydroxyl group. Preferred pentapeptides of formula (7g) include: (SEQNO:90) 4-F-Phe-3,4-Dehydro-Pro-Arg-Gly-4-F-Trp-NH₂ (SEQ NO:91)4-F-Phe-3,4-Dehydro-Pro-Arg-Gly-5-F-Trp-NH₂ (SEQ NO:92)4-F-Phe-3,4-Dihydro-Pro-Arg-Gly-6-F-Trp-NH₂ (SEQ NO:93)4-F-Phe-3,4-Dehydro-Pro-Arg-Gly-3-CH₃O-Trp-NH₂ (SEQ NO:94)4-F-Phe-3,4-Dehydro-Pro-Arg-Gly-N-Methyl-Trp-NH₂ (SEQ NO:95)4-F-Phe-3,4-Dehydro-Pro-Arg-Gly-1-Methyl-Trp-NH₂ (SEQ NO:96)4-F-Phe-3,4-Dehydro-Pro-Arg-Gly-4-Methyl-Trp-NH₂ (SEQ NO:97)4-F-Phe-3,4-Dehydro-Pro-Arg-Gly-5-Methyl-Trp-NH₂ (SEQ NO:98)4-F-Phe-3,4-Dehydro-Pro-Arg-Gly-6-Methyl-Trp-NH₂ (SEQ NO:99)4-F-Phe-3,4-Dehydro-Pro-Arg-Gly-5-Hydroxy-Trp-NH₂.

[0177] In yet another embodiment of the invention, pentapeptidecompositions or pharmaceutically acceptable salts thereof includingaddition of a C-terminus amino acid and an internal amino acid can berepresented by the following formula (8):

R¹-Pro¹-AA¹-AA²-Gly-AA³-R   (8)

[0178] where Pro¹ represents the amino acid Pro or dehydro-Pro,preferably 3,4-dehydro-Pro; AA¹ and AA² each independently represent anamino acid of the group of Leu or Ile; AA³ represents Trp; R representsa carboxyl group, a hydroxyalkyl group, a carbamyl group, analkylcarbamyl group, or an alkoxycarbonyl group; and, R¹ represents ahydrogen atom, a lower alkyl group, preferably having 1 to 3 carbonatoms, a halogen atom, preferably a fluorine or chlorine atom, ahydroxyl group, preferably a cis- or trans-4-OH— group, a sulphydrylgroup, preferably a cis- or trans-4-thio- group, or an alkylamino ordialkylamino group, preferably a methyl or ethylamino group or dimethylor diethylamino group.

[0179] Preferred compositions of the pentapeptides of formula (8) whichmay be utilized alone or in combination with other peptides disclosedherein to treat patients suffering from physiological, psychosomatic,neurological or psychiatric disorders are characterized by addition of aC-terminus amino acid of Trp to Gly, addition of an internal amino acidof Leu or Ile between Pro¹ and Gly, optional modification of theheterocyclic nitrogen ring of Pro¹, optional replacement of Leu withIle, and by having the C-terminus amide remain unmodified, which can berepresented by formula (8a):

R¹-Pro¹-AA¹-AA²-Gly-Trp-NH₂   (8a)

[0180] wherein Pro¹, AA¹, AA², and R¹ are as described for formula (8).Preferred pentapeptides of formula (8a) are:

Pro-Ile-Leu-Gly-Trp-NH₂ (SEQ ID NO: 44),

[0181] and,

cis- or trans-4-OH-Pro-Ile-Leu-Gly-Trp-NH₂ (SEQ ID NO: 45).

[0182] In another embodiment of the invention, pentapeptide compositionsor pharmaceutically acceptable salts thereof including addition of botha N-terminus amino acid and a C-terminus amino acid can be representedby the following formula (9):

R¹-AA¹-R²-Pro¹-AA²-Gly-AA³-R   (9)

[0183] where Pro¹ represents the amino acid Pro or dehydro-Pro,preferably 3,4-dehydro Pro; AA¹ represents the amino acid Ala; AA²represents an amino acid of the group of Leu, Ile, Arg, D-Arg, Trp, orcanavanine; AA³ represents the amino acid Trp; R represents a carboxylgroup, hydroxyalkyl group, a carbamyl group, an alkylcarbamyl group, oran alkoxycarbonyl group; and, R¹ represents a pyridyl ring, preferablyas a 3-(3-pyridyl) moiety; R² represents a hydrogen atom, a lower alkylgroup, preferably having 1 to 3 carbon atoms, a halogen atom, preferablya fluorine or chlorine atom, a hydroxyl group, preferably a cis- ortrans-4-OH— group, a sulphydryl group, preferably a cis- ortrans-4-thio- group, or an alkylamino or dialkylamino group, preferablya methyl or ethylamino or dimethyl or diethylamino group.

[0184] A preferred composition of formula (9) includes but is notlimited to:

3-(3-pyridyl)-Ala-4-OH-Pro-Arg-Gly-Trp-NH₂ (SEQ ID NO: 70).

[0185] In another embodiment of the invention, hexapeptide compositionsor pharmaceutically acceptable salts thereof including addition of botha N-terminus amino acid and a C-terminus amino acid can be representedby formula (10):

R¹-AA¹-R²-Pro¹-AA²-AA⁴-Gly-AA³-R   (10)

[0186] where Pro¹ represents the amino acid Pro or dehydro-Pro; AA¹represents an amino acid of the group of Phe or Tyr; AA² represents anamino acid of the group of Leu, Ile, Arg, D-Arg, Trp, or canavanine; AA³represents the amino acid Trp; AA⁴ represents the amino acid Gly or Ile;R represents a carboxyl group, hydroxyalkyl group, a carbamyl group, analkylcarbamyl group, or an alkoxycarbonyl group; and, R¹ and R² eachindependently represent a hydrogen atom, a lower alkyl group, preferablyhaving 1 to 3 carbon atoms, a halogen atom, preferably a fluorine orchlorine atom, a hydroxyl group, preferably a cis- or trans-4-OH— group,a sulphydryl group, preferably a cis- or trans-4-thio- group, or analkylamino or dialkylamino group, preferably a methyl or ethylamino ordimethyl or diethylamino group.

[0187] A preferred composition of formula (10) is4-F-Phe-3,4-Dehydro-Pro-Arg-Gly-Gly-Trp-NH₂ (SEQ NO: 80).

[0188] Preferred hexapeptides of formula (10) which may be utilizedalone or in combination with other peptides disclosed herein to treatpatients suffering from physiological, psychosomatic, neurological orpsychiatric disorders are characterized by addition of a C-terminusamino acid of Trp, optional modification of the heterocyclic nitrogenring of Pro¹, preferably a cis- or trans-4-OH group, a fluorine atom atposition 4 of Phe; preferably Arg at AA²; Tpr at AA³; and Ile or Gly atAA⁴, and by having the C-terminus amide remain unmodified, which can berepresented by formula (10a):

R¹-Phe-R²-Pro¹-AA²-AA⁴⁻Gly-Trp-NH₂   (10a)

[0189] wherein preferred peptides of formula (10a) are: (SEQ ID NO:58)4-F-Phe-4-OH-Pro-Arg-Gly-Gly-Trp-NH₂; and (SEQ ID NO:67)4-F-Phe-4-OH-Pro-Arg-Ile-Gly-Trp-NH₂.

[0190] In another embodiment of the invention, heptapeptide compositionsor pharmaceutically acceptable salts thereof including addition of botha N-terminus amino acid and a C-terminus amino acid can be representedby the following formula (11):

R¹-AA¹-R²-Pro¹-AA²-AA⁴-AA⁵-Gly-AA³-R   (11)

[0191] where Pro¹ represents the amino acid Pro or dehydro-Pro; AA¹represents an amino acid of the group of Phe or Tyr; AA² represents anamino acid of the group of Leu, Ile, Arg, D-Arg, Trp, or canavanine; AA³represents the amino acid Trp; AA⁴ and AA⁵ represent the amino acid Glyor Ile; R represents a carboxyl group, hydroxyalkyl group, a carbamylgroup, an alkylcarbamyl group, or an alkoxycarbonyl group; and, R¹ andR² each independently represent a hydrogen atom, a lower alkyl group,preferably having 1 to 3 carbon atoms, a halogen atom, preferably afluorine or chlorine atom, a hydroxyl group, preferably a cis- ortrans-4-OH— group, a sulphydryl group, preferably a cis- ortrans-4-thio- group, or an alkylamino or dialkylamino group, preferablya methyl or ethylamino or dimethyl or diethylamino group, or a phosphonogroup (preferably as phosphono-Tyr).

[0192] A preferred composition of formula (11) is:

4-F-Phe-4-OH-Pro-Arg-Gly-Ile-Gly-Trp-NH₂ (SEQ ID NO: 56).

[0193] Preferred tetrapeptides of formula (12) or pharmaceuticallyacceptable salts thereof which may be utilized alone or in combinationwith other peptides disclosed herein to treat patients suffering fromphysiological, psychosomatic, neurological or psychiatric disorders arecharacterized by replacement of Pro with Arg; addition of an N-terminusamino acid of Phe to Arg; addition of a C-terminus amino acid of Trp toGly; optional modification of the aromatic rings of Phe and by havingthe C-terminus amide remain unmodified, which can be represented byformula (12):

R¹-Phe-R²-Arg-Gly-Trp-NH₂   (12)

[0194] where R¹ represents a halogen atom and R² represents a carboxylicacid of a monocyclic organic compound with a three to six membered ringstructure having a hetero nitrogen atom. Preferred compositions of thepentapeptides of formula (12) include, but are not necessarily limitedto: 4-F-Phe-isonipecotic acid-Arg-Gly-Trp-NH₂(4-pyridinecarboxylic acid)(SEQ NO:100) 4-F-Phe-2-Carboxy-Azetidine-Arg-Gly-Trp-NH₂ (SEQ NO:101)4-F-Phe-2-carboxy-Aziridine-Arg-Gly-Trp-NH₂ (SEQ NO:103)4-F-Phe-3-Carboxy-1,4,5,6-Tetrahydropyridine-Arg-Gly-Trp-NH₂ (SEQNO:105) 4-F-Phe-2-Carboxypyrrole-Arg-Gly-Trp-NH₂. (SEQ NO:106)

[0195] The following paragraph discloses compositions of thepentapeptides of formula (13), which may be utilized alone or incombination with other peptides disclosed herein to treat patientssuffering from physiological, psychosomatic, neurological or psychiatricdisorders.

[0196] Preferred compositions of the pentapeptides of formula (13) or apharmaceutically acceptable salt thereof which may be utilized alone orin combination with other peptides disclosed herein to treat patientssuffering from physiological, psychosomatic, neurological or psychiatricdisorders are characterized by replacement of Pro with Arg; addition ofan N-terminus amino acid of Phe to Arg; addition of an internal aminoacid; addition of a C-terminus amino acid of Trp to Gly; optionalmodification of the aromatic ring of Phe and by C-terminus amideremaining unmodified, which can be represented by formula (13). Formula(13) is depicted as:

R¹-Phe-AA¹-Arg-Gly-Trp-NH₂   (13)

[0197] where AA¹ represents an amino acid selected from the groupcomprising 1-amino-1-carboxycyclopentane and1-amino-1-carboxy-cyclopropyl and R¹ represents a halogen atom.Preferred compositions of the pentapeptides of formula (13) include, butare not necessarily limited to,4-F-Phe-1-Amino-1-Carboxycyclopentane-Arg-Gly-Trp-NH₂ (SEQ NO: 102) and4-F-Phe-1-Amino-1-Carboxy-Cyclopropyl-Arg-Gly-Trp-NH₂ (SEQ NO: 104).

[0198] In some embodiments, Gly in compounds of formula (7) throughformula (11) may be replaced with Val or Ala. One preferred peptidecomposition wherein Gly is substituted with Sar in formula (7) is4-F-Phe-3,4-Dehydro-Pro-Arg-Sar-Trp-NH₂ (SEQ NO: 110).

[0199] In yet another embodiment of the invention, the peptides arepolypeptides including chemical combinations and/or overlapping chemicalcombinations of any of the peptides of any of formula (1) throughformula (11) described above which may be utilized alone or incombination with other peptides disclosed herein to treat patientssuffering from physiological, psychosomatic, neurological or psychiatricdisorders. The chemical combinations and/or overlapping chemicalcombinations of the peptides disclosed preferably range from at leastabout three to at least about ten amino acids. Examples of suchcombinations include: 4-F-Phe-cis- or trans-4-OH-Pro-Ile-Gly-Trp-Gly-NH2(SEQ ID NO: 46); 4-F-Phe-cis or trans-4-OH-Pro-Ile-Gly-Trp-Gly-Trp-NH₂(SEQ ID NO: 47); 4-F-Phe-cis- or trans-4-OH-Pro-Leu-Gly-Trp-Gly-NH₂ (SEQID NO: 48); 4-F-Phe-cis- or trans-4-OH-Pro-Leu-Gly-Trp-Gly-Trp-NH₂ (SEQID NO: 49); Pro-Ile-Gly-Trp-Pro-Ile-Gly-NH₂; (SEQ ID NO: 50)4-F-Phe-cis- or trans-4-OH-Pro-Arg-Gly-Trp-Gly-NH₂ (SEQ ID NO: 51);4-F-Phe-cis or trans-4-OH-Pro-Arg-Gly-Trp-Gly-Trp-NH₂ (SEQ ID NO: 52);cis- or trans-4-OH-Pro-Ile-Gly-cis- or trans-4-OH-Pro-Ile-Gly-NH₂ (SEQID NO: 53); 3,4-dehydro-Pro-D-Arg-Gly-3,4-dehydro-Pro-D-Arg-Gly-NH₂;3,4-dehydro-Pro-D-Arg-Gly-Trp-Gly-NH₂; and3,4-dehydro-Pro-D-Arg-Gly-Trp-Gly-Trp-NH₂.

[0200] Especially preferred compositions of the present invention arepeptides that show higher activity in the Porsolt swim test than knowncompounds used to treat anxiety and/or depression. These peptides mayvary in length, with the preferred peptides being tetrapeptides,pentapeptides, hexapeptides and heptapeptides. A general formula forthese especially preferred peptides, which are disclosed throughout thisspecification, is:

R¹-Phe-Pro¹-AA²-AA³-NH₂,

[0201] for a tetrapeptide, wherein R¹ is preferably a halogen atom, mostpreferably a fluorine or chlorine atom, a carboxyl group, an amino groupor a nitro group, with all modifications preferably at the C4 atom ofPhe; Pro¹ is 3,4-dehydro Pro, Homo-Pro, cis- or trans-4OH-Pro or Pro, aslisted in order of preference, AA² is preferably Ile, Leu or Arg; andAA³ is preferably Gly or Trp.

[0202] Another preferred tetrapeptide of the present invention isPro-Ile-Gly-Trp (SEQ ID NO: 3).

[0203] The formula for the especially preferred pentapeptides,hexapeptides and heptapeptides, which are also disclosed throughout thisspecification, may be:

R¹-Phe-Pro¹-AA²-Gly-AA_((n))-AA³-NH₂,

[0204] wherein R¹ is preferably a halogen atom, preferably a fluorine orchlorine atom, a carboxyl group, an amino group or a nitro group, withall modifications preferably at the C4 atom of Phe; Pro¹ is 3,4-dehydroPro, Homo-Pro, cis- or trans-4OH-Pro or Pro, as listed in order ofpreference, AA² is preferably Arg, Ile, Leu or His, with Arg beingespecially preferred; AA_((n)) is 0-2 amino acid residues, if n=1, thenGly is preferred and if n=2, then Ile-Gly, Ile-Ile or Gly-Gly ispreferred; AA³ is preferably Trp or Gly, with Trp most preferred.

[0205] The present invention further provides admixtures of the peptidesof formula (1) through formula (11) with known antidepressant compoundssuch as amitriptyline, fluoxetine (Prozac) and sertraline (Zoloft). Itis within the ordinary skill of the artisan to generate variousadmixtures with the peptides of the present invention beyond theexemplifications disclosed throughout this specification.

[0206] The peptides with which this invention is concerned are readilyprepared by conventional procedures (i.e., carbodiimide method, mixedanhydride method, N, N-carbonyldiimidazole method) for the step-wisesynthesis of polypeptides, and also including solid phase peptidesynthesis. The substituent groups are also readily added to thepolypeptide residues by conventional procedures.

[0207] While it is not intended that the present invention be bound byany particular theory or mechanism, it is believed that certain of thepeptides disclosed herein function to treat physiological,psychosomatic, neurological and/or psychiatric disorders at least inpart by binding to serotonin receptors and to neuropeptide Y receptorsin the brain of a patient to whom the peptides are administered. Forexample, experimental work has shown that the compounds having theformula 4-F-Phe- trans-4-OH-Pro-Arg-Gly-Trp-NH₂ (SEQ ID NO: 43),following subcutaneous administration to rats, are found at detectablelevels and substantially unchaged in the hippocampus and the amygdala,which are known to be sites of receptors including 5-HT and neuropeptideY receptors, and which receptors are known to be involved in depressionand its treatment. Additional experimental work has shown that peptidecompounds disclosed herein interact with the serotonin releaserd-fenfluramine, and may act as a 5-HT 2A antagonist, indicating that themechanism of action of the peptide compounds involves the serotonergicpathway, in a different way from that of the SSRIs. While it is notintended that the present invention be bound by any particular theory,it is believed that certain of the peptides disclosed herein function totreat physiological, psychosomatic, neurological or psychiatricdisorders in a patient by administering to the patient one or morepeptide compounds that bind to at least one of 5-HT and neuropeptide Yreceptors in the brain of the patient. The present invention furtherprovides methods and compositions for treating physiological,psychosomatic, neurological or psychiatric disorders in a patient byadministering to the patient one or more peptide compounds that involvein their mechanism of action, at least in part, the serotonergic and/orneuropetide Y-ergic pathway. In preferred embodiments, the peptidecompounds that are acting, at least in part, via the serotenergic and/orneuropetide Y-ergic pathway are effective in treating anxiety. In highlypreferred embodiments, the peptide compounds that are acting, at leastin part, via the serotenergic and/or neuropetide Y-ergic pathway have aformula 4-F-Phe-cis- or trans-4-OH-Pro-Arg-Gly-Trp-NH₂ (SEQ ID NO: 43).

[0208] The peptides of the invention possess antidepressant activity asdetermined by the Porsolt swim test. The procedure used is described inthe Examples hereinbelow. The Porsolt swim test is based on theobservation that when a rat is forced to swim in a situation from whichthere is no escape, the rat ceases to move altogether and makes onlythose movements necessary to keep its head above water. Immobilityindicates a state of despair. Therefore, a compound with activity as anantidepressant will delay the onset of immobility.

[0209] Compositions disclosed herein may be administered in a variety offormulations, in which the peptides disclosed herein are the “activeingredient”, and which may include other ingredients, as well asadditives and processing aids known in the art. The active ingredientmay be formulated in combination with such other agents as, for example,local anesthetics and therapeutic agents. The other agents may be mixedin the compositions and administered prior to, simultaneously with orsubsequent to administration of the compositions provided for themethods herein.

[0210] The active ingredient, which may comprise one or more of thepeptides disclosed herein, maybe formulated in a suitable pharmaceuticalcarrier for in vivo administration to the patient by any standard methodknown in the art. Appropriate routes of administration of thecompositions include oral, sublingual, parenteral (e.g., intravenous,intraspinal, intrathecal, intraventricular, epidermal, intracisternal,intracutaneous or intradermal, subcutaneous, or intramuscular),epicutaneous or transdermal, intranasal, rectal or vaginal. Thecompositions may be formulated as injectables, as oral or rectalformulations for systemic administration; and for local and topicaladministration as creams, aqueous or nonaqueous suspension, lotions,emulsions, suspensions or emulsions containing micronized particles,gels, foams, aerosols, solids and other suitable vehicles forapplication to the skin, eyes, lips and mucosa; as suppositories orcream for vaginal administration, and as combinations with bandages,patches, bioadhesives and dressings.

[0211] Oral administration routes include capsules, solutions,suspensions, gels, powders, elixirs and syrups. Sublingualadministration routes include tablets, solutions, suspensions, elixirs,syrups, and lozenges. Parenteral administration routes include solutionsand suspensions. Epicutaneous or transdermal administration routesinclude, but are not necessarily limited to, ointments, creams, pastes,plasters, powders, aerosols, lotions, transdermal patches, discs andsolutions. Intranasal administration routes include solutions, sprays,inhalants or ointments. Rectal administration routes include ointmentsand suppositories. The active ingredient may also be formulated forincorporation into liposomes, microcapsules, or into polymer orwax-based preparations, which may be for controlled release. Additionalguidance regarding routes of administration and the generation ofpharmaceutically effective dose rates may be found in “Dosage FormDesign: Biopharmaceutical Considerations” in Pharmaceutical Dosage Formsand Drug Delivery Systems, Chapter 3, Ansel, H. C. and Popovich, N. G.,Fifth Ed.; Lea and Febiger, Philadelphia (1990).

[0212] The concentration of the peptide(s) used in any of theaforementioned formulations will depend upon the effective dose and themode of administration used to elicit the appropriate biological effect.The dose should be sufficient to achieve circulating plasmaconcentrations of the active ingredient such that effective amountscross the blood-brain barrier that are efficacious. For example, whenthe tetrapeptide Pro-Leu-Gly-Trp-NH₂ is the active ingredient, acirculating plasma level from about 30 mg to about 90 mg per averageadult may be used; preferably about 60 mg per average adult. Effectivedoses for various routes of administration may be extrapolated fromdose-response curves derived from in vitro or animal model test systems.

[0213] The methods and compositions disclosed herein are useful intreating patients suffering from a variety of physiological,psychosomatic, neurological or psychiatric disorders. For example, themethods and compositions disclosed herein are useful in treatingpatients suffering from anxiety disorder, including anxiety engenderedor exacerbated by the use of certain medications by the patient. Somepatients exhibit anxiety when administered certain antidepressantmedications, particularly SSRIs such as fluoxetine. The effects of somemedications in causing or exacerbating anxiety are referred to as“anxiogenic effects”. It has been found that peptides disclosed hereinmay reduce or alleviate anxiogenic effects of antidepressant medicationssuch as fluoxetine. It has further been found that peptides disclosedherein can be used to treat anxiety in patients suffering from anxietydisorder, or anxiety disorder in conjunction with depression. Preferredpeptides for use in treatment of anxiety include compounds disclosedherein and having formulas 4-F-Phe-cis- ortrans-4-OH-Pro-Arg-Gly-Trp-NH₂ (SEQ ID NO: 43).

[0214] The invention will be further clarified by a consideration of thefollowing examples, which are intended to be purely exemplary of thesynthesis and use of the peptides of the invention. Peptides disclosedherein provide antidepressant activity as measured in the Porsolt swimtest. The Example Section contains data comparing exemplified peptidesdisclosed herein with known antidepressants amitriptyline, fluoxetineand sertraline generated in a series of Porsolt swim tests.

EXAMPLES Example 1

[0215] Effectiveness of Peptide Compounds in Treating Anxiety

[0216] The effectiveness of peptide compounds in treating anxiety can beconfirmed using tests performed on rats. The tests include a socialinteraction test and an elevated maze test. Detailed procedures for thetests are described in Gonzalez et al., “Selectively bred lines of ratdiffer in social interaction and hippocampal 5-HT1A receptor function: Alink between anxiety and depression?”, Pharmacol. Biochem. Behav. 59:787-792 (1998); and File et al., “Chronic fluoexitine in tests ofanxiety in rat lines selectively bred for differential 5-HT1A receptorfunction”. Pharmacol. Biochem. Behav. 62: 695-701 (1999), thedisclosures of which are herein incorporated by reference in theirentirety.

[0217] Thirty-two rats are used in the tests, divided into groups of 8to be used in 4 experiments. Flinders Sensitive Line (FSL) rats are usedin these examples. FSL rats are genetically predisposed to be sensitiveto antidepressive agents. They resemble depressed humans in that theyhave elevated REM sleep, appetite and weight changes, reduced activity,and increased anhedonia after exposure to stressors. FSL rats alsoexhibit exaggerated immobility in the Porsolt swim test, which iscounteracted by both tricyclic antidepressants and serotonin reuptakeinhibitors.

[0218] Group I is administered chronic doses of a pharmaceuticallyacceptable vehicle for injectable medication for 21 days, then a singleinjection of the vehicle alone 30 minutes prior to being submitted to asocial interaction test. Group II is administered chronic doses of thevehicle alone for 21 days, then 5 mg/kg of fluoxetine 30 minutes priorto the social interaction test. Group III is administered 0.2 mg/kg ofthe compound being tested for 21 days, then a single injection of thevehicle alone prior to the social interaction test. Group IV isadministered 0.2 mg/kg of the test compound for 21 days, then a singleinjection of 5 mg/kg of fluoxetine 30 minutes prior to the socialinteraction test.

[0219] For the social interaction test, the rats are placed into asquare, open field, 2 ft×2 ft, with 16 squares marked out in the field.The rats are not familiar with the field, and low lighting conditionsare imposed. Rats are paired on the basis of body weight and treatmentconditions, and each pair is placed into the field for 5 minutes. Ratsare observed, and scored on the basis of time spent in socialinteraction (e.g., grooming, sniffing, following), and the number oftimes each rat crosses a line by two forepaws.

[0220] The elevated maze test is conducted 2 to 9 minutes after thesocial interaction test. The maze is made of black perspex and comprisestwo opposing closed arms and two opposing open arms, with a centralarena between the arms. The arms are elevated 50 cm from the ground, andthe central arena is at ground level. The central arena measures 10×10cm. Each rat being tested is placed separately in the maze with its headin the central arena. The rats are observed and measurements are takenof the number of entries into the closed arms of the maze by the entirerat (an indicator of activity) and time spent in the open arms of themaze by at least two forepaws (an indicator of anxiety).

Example 2

[0221] Measurement of Anxiolytic and Antidepressant Effects of PeptideCompounds

[0222] This example tests whether chronic treatment with compounds knownto have antidepressive effects also modifies social interactionbehavior, thereby indicating whether the compounds have anxiolyticeffects. Eighteen FSL rats are used. Ten rats are treated with 0.2 mg/kgof a test compound in an injection vehicle daily for 14 days. Eight ratsare treated only with the injection vehicle. Approximately 22 hoursafter the last treatment, each rat is separately placed into a socialaction arena for 5 minutes. Line crossings by forepaws and socialinteraction are recorded.

[0223] Immediately following the social interaction test, each rate issubjected to the Porsolt swim test. Each rat is placed into a cylinderof 25° C. water for 5 minutes. Latency and swimming are recordedaccording to known procedures for the Porsolt test.

[0224] Other embodiments of the invention will be apparent to thosepersons skilled in the art from a consideration of this specification orpractice of the invention disclosed herein. It is intended that thespecification and examples be considered as exemplary only, with thetrue scope and spirit of the invention to which exclusive rights areclaimed being assessed by the appended claims.

1 128 4 amino acids amino acid single linear peptide Modified_site 1/label= 4Hyp /note= “Amino acid #1 is either cis_ or trans_ 4Hyp”Modified_site 4 /label= Trp_NH2 /note= “A modified Trp residue an aminegroup replaces a hydroxyl group at the carboxy terminus.” 1 Xaa Leu GlyXaa 1 4 amino acids amino acid single linear peptide Modified_site 1/label= 4Hyp /note= “Amino acid #1 is either cis_ or trans_ 4Hyp.”Modified_site 4 /label= Trp_NH2 /note= “Amino acid #4 is a modified Trpresidue an amine group replaces a hydroxyl group at the carboxyterminus.” 2 Xaa Ile Gly Xaa 1 4 amino acids amino acid single linearpeptide Modified_site 4 /label= Trp_NH2 /note= “A modified Trp residuean amine group replaces a hyroxyl group at the carboxy terminus.” 3 ProIle Gly Xaa 1 4 amino acids amino acid single linear peptideModified_site 1 /label= 3_4DeH_Pro /note= “Proline residue with a C3=C4double bond.” Modified_site 4 /label= Trp_NH2 /note= “A modified Trpresidue an amide group replaces a hydroxyl group at the carboxyterminus.” 4 Xaa Ile Gly Xaa 1 4 amino acids amino acid single linearpeptide Modified_site 4 /label= Trp_NH2 /note= “A modified Trp residuean amine group replaces a hydroxyl group at the carboxy terminus.” 5 ProLeu Gly Xaa 1 4 amino acids amino acid single linear peptideModified_site 4 /label= Tyr_NH2 /note= “A modified Tyr residue an aminegroup replaces a hydroxyl group at the carboxy terminus.” 6 Pro Leu GlyXaa 1 4 amino acids amino acid single linear peptide Modified_site 4/label= Trp_NH2 /note= “A modified Trp residue an amine group replaces ahydroxyl group at the carboxy terminus.” 7 Pro Arg Gly Xaa 1 4 aminoacids amino acid single linear peptide Modified_site 4 /label= Trp_NH2/note= “A modified Trp residue an amine group replaces a hydroxyl groupat the carboxy terminus.” 8 Pro Trp Gly Xaa 1 4 amino acids amino acidsingle linear peptide Modified_site 4 /label= Tyr_NH2 /note= “A modifiedTyr residue an amine group replaces a hydroxyl group at the carboxyterminus.” 9 Pro Ile Gly Xaa 1 4 amino acids amino acid single linearpeptide Modified_site 4 /label= Gly_NH2 /note= “A modified Gly residuean amine group replaces a hydroxyl group at the carboxy terminus.” 10Trp Pro Leu Xaa 1 4 amino acids amino acid single linear peptideModified_site 4 /label= Gly_NH2 /note= “A modified Gly residue an aminegroup replaces a hydroxyl group at the carboxy terminus.” 11 Phe Pro LeuXaa 1 4 amino acids amino acid single linear peptide Modified_site 1/label= 4F_Phe /note= “Phe residue modified at C4 with a fluorine atom.”Modified_site 4 /label= Gly_NH2 /note= “A modified Gly residue an aminegroup replaces a hydroxyl group at the carboxy terminus.” 12 Xaa Pro LeuXaa 1 4 amino acids amino acid single linear peptide Modified_site 1/label= 4Cl_Phe /note= “Phe residue modified at C4 with a chlorineatom.” Modified_site 4 /label= Gly_NH2 /note= “A modified Gly residue anamine group replaces a hydroxyl group at the carboxy terminus.” 13 XaaPro Leu Xaa 1 4 amino acids amino acid single linear peptideModified_site 1 /label= 4F_Phe /note= “Phe residue modified at C4 with afluorine atom.” Modified_site 4 /label= Gly_NH2 /note= “A modified Glyresidue an amine group replaces a hydroxyl group at the carboxyterminus.” 14 Xaa Pro Ile Xaa 1 4 amino acids amino acid single linearpeptide Modified_site 1 /label= 4F_Phe /note= “Phe residue modified atC4 with a fluorine atom.” Modified_site 2 /label= 4Hyp /note= “Aminoacid #2 is either cis_ or trans_ 4Hyp.” Modified_site 4 /label= Gly_NH2/note= “A modified Gly residue an amine group replaces a hydroxyl groupat the carboxy terminus.” 15 Xaa Xaa Leu Xaa 1 4 amino acids amino acidsingle linear peptide Modified_site 1 /label= 4F_Phe /note= “Phe residuemodified at C4 with a fluorine atom.” Modified_site 2 /label= 4Hyp/note= “Amino acid #2 is either cis_ or trans_ 4Hyp.” Modified_site 4/label= Gly_NH2 /note= “A modified Gly residue an amine group replaces ahydroxyl group at the carboxy terminus.” 16 Xaa Xaa Ile Xaa 1 4 aminoacids amino acid single linear peptide Modified_site 4 /label= Gly_NH2/note= “A modified Gly residue an amine group replaces a hydroxyl groupat the carboxy terminus.” 17 Trp Pro Leu Xaa 1 4 amino acids amino acidsingle linear peptide Modified_site 4 /label= Gly_NH2 /note= “A modifiedGly residue an amine group replaces a hydroxyl group at the carboxyterminus.” 18 Trp Pro Ile Xaa 1 4 amino acids amino acid single linearpeptide Modified_site 2 /label= 4Hyp /note= “Amino acid #2 is eithercis_ or trans_ 4Hyp.” Modified_site 4 /label= Gly_NH2 /note= “A modifiedGly residue an amine group replaces a hydroxyl group at the carboxyterminus.” 19 Trp Xaa Leu Xaa 1 4 amino acids amino acid single linearpeptide Modified_site 2 /label= 4Hyp /note= “Amino acid #2 is eithercis_ or trans_ 4Hyp.” Modified_site 4 /label= Gly_NH2 /note= “A modifiedGly residue an amine group replaces a hydroxyl group at the carboxyterminus.” 20 Trp Xaa Ile Xaa 1 5 amino acids amino acid single linearpeptide Modified_site 1 /label= 4F_Phe /note= “Phe modified at C4 with afluorine atom.” Modified_site 5 /label= Gly_NH2 /note= “A modified Glyresidue an amine group replaces a hydroxyl group at the carboxyterminus.” 21 Xaa Tyr Pro Leu Xaa 1 5 5 amino acids amino acid singlelinear peptide Modified_site 1 /label= 4Cl_Phe /note= “Phe residuemodified at C4 with a chlorine atom.” Modified_site 5 /label= Gly_NH2/note= “A modified Gly residue an amine group replaces a hydroxyl groupat the carboxy terminus.” 22 Xaa Tyr Pro Leu Xaa 1 5 5 amino acids aminoacid single linear peptide Modified_site 5 /label= Gly_NH2 /note= “Amodified Gly residue an amine group replaces a hydroxyl group at thecarboxy terminus.” 23 Phe Tyr Pro Leu Xaa 1 5 5 amino acids amino acidsingle linear peptide Modified_site 5 /label= Gly_NH2 /note= “A modifiedGly residue an amine group replaces a hydroxyl group at the carboxyterminus.” 24 Phe Tyr Pro Ile Xaa 1 5 5 amino acids amino acid singlelinear peptide Modified_site 3 /label= 4Hyp /note= “Amino acid #3 iseither cis_ or trans_ 4Hyp.” Modified_site 5 /label= Gly_NH2 /note= “Amodified Gly residue an amine group replaces a hydroxyl group at thecarboxy terminus.” 25 Phe Tyr Xaa Leu Xaa 1 5 5 amino acids amino acidsingle linear peptide Modified_site 3 /label= 4Hyp /note= “Amino acid #3is either cis_ or trans_ 4Hyp.” Modified_site 5 /label= Gly_NH2 /note=“A modified Gly residue an amine group replaces a hydroxyl group at thecarboxy terminus.” 26 Phe Tyr Xaa Ile Xaa 1 5 5 amino acids amino acidsingle linear peptide Modified_site 5 /label= Gly_NH2 /note= “A modifiedGly residue an amine group replaces a hydroxyl group at carboxyterminus.” 27 Tyr Tyr Pro Leu Xaa 1 5 5 amino acids amino acid singlelinear peptide Modified_site 5 /label= Gly_NH2 /note= “A modified Glyresidue an amine group replaces a hydroxyl group at the carboxyterminus.” 28 Tyr Tyr Pro Ile Xaa 1 5 5 amino acids amino acid singlelinear peptide Modified_site 3 /label= 4Hyp /note= “Amino acid #3 iseither cis_ or trans_ 4Hyp.” Modified_site 5 /label= Gly_NH2 /note= “Amodified Gly residue an amine group replaces a hydroxyl group at thecarboxy terminus.” 29 Tyr Tyr Xaa Leu Xaa 1 5 5 amino acids amino acidsingle linear peptide Modified_site 3 /label= 4Hyp /note= “Amino acid #3is either cis_ or trans_ 4Hyp.” Modified_site 5 /label= Gly_NH2 /note=“A modified Gly residue an amine group replaces a hydroxyl group at thecarboxy terminus.” 30 Tyr Tyr Xaa Ile Xaa 1 5 5 amino acids amino acidsingle linear peptide Modified_site 5 /label= Trp_NH2 /note= “A modifiedTrp residue an amine group replaces a hydroxyl group at the carboxyterminus.” 31 Phe Pro Leu Gly Xaa 1 5 5 amino acids amino acid singlelinear peptide Modified_site 5 /label= Trp_NH2 /note= “A modified Trpresidue an amine group replaces a hydroxyl group at the carboxyterminus.” 32 Tyr Pro Leu Gly Xaa 1 5 5 amino acids amino acid singlelinear peptide Modified_site 2 /label= 4Hyp /note= “Amino acid #2 iseither cis_ or trans_ 4Hyp.” Modified_site 5 /label= Trp_NH2 /note= “Amodified Trp residue an amine group replaces a hydroxyl group at thecarboxy terminus.” 33 Phe Xaa Leu Gly Xaa 1 5 5 amino acids amino acidsingle linear peptide Modified_site 5 /label= Trp_NH2 /note= “A modifiedTrp residue an amine group replaces a hydroxyl group at the carboxyterminus.” 34 Phe Pro Ile Gly Xaa 1 5 5 amino acids amino acid singlelinear peptide Modified_site 2 /label= 4Hyp /note= “Amino acid #2 iseither cis_ or trans_ 4Hyp.” Modified_site 5 /label= Trp_NH2 /note= “Amodified Trp residue an amine group replaces a hydroxyl group at thecarboxy terminus.” 35 Phe Xaa Ile Gly Xaa 1 5 5 amino acids amino acidsingle linear peptide Modified_site 2 /label= 4Hyp /note= “Amino acid #2is either cis_ or trans_ 4Hyp.” Modified_site 5 /label= Trp_NH2 /note=“A modified Trp residue an amine group replaces a hydroxyl group at thecarboxy terminus.” 36 Tyr Xaa Leu Gly Xaa 1 5 5 amino acids amino acidsingle linear peptide Modified_site 5 /label= Trp_NH2 /note= “A modifiedTrp residue an amine group replaces a hydroxyl group at the carboxyterminus.” 37 Tyr Pro Ile Gly Xaa 1 5 5 amino acids amino acid singlelinear peptide Modified_site 2 /label= 4Hyp /note= “Amino acid #2 iseither cis_ or trans_ 4Hyp.” Modified_site 5 /label= Trp_NH2 /note= “Amodified Trp residue an amine group replaces a hydroxyl group at thecarboxy terminus.” 38 Tyr Xaa Leu Gly Xaa 1 5 5 amino acids amino acidsingle linear peptide Modified_site 5 /label= Trp_NH2 /note= “A modifiedTrp residue an amine group replaces a hydroxyl group at the carboxyterminus.” 39 Tyr Pro Trp Gly Xaa 1 5 5 amino acids amino acid singlelinear peptide Modified_site 2 /label= 4Hyp /note= “Amino acid #2 iseither cis_ or trans_ 4Hyp.” Modified_site 5 /label= Trp_NH2 /note= “Amodified Trp residue an amine group replaces a hydroxyl group at thecarboxy terminus.” 40 Tyr Xaa Trp Gly Xaa 1 5 5 amino acids amino acidsingle linear peptide Modified_site 1 /label= 4F_Phe /note= “Phe residuemodified at C4 with a fluorine atom.” Modified_site 2 /label= 4Hyp/note= “Amino acid #2 is either cis_ or trans_ 4Hyp.” Modified_site 5/label= Trp_NH2 /note= “A modified Trp residue an amine group replaces ahydroxyl group at the carboxy terminus.” 41 Xaa Xaa Ile Gly Xaa 1 5 5amino acids amino acid single linear peptide Modified_site 1 /label=4F_Phe /note= “Phe residue modified at C4 with a fluorine atom.”Modified_site 2 /label= 4Hyp /note= “Amino acid #2 is either cis_ ortrans_ 4Hyp.” Modified_site 5 /label= Trp_NH2 /note= “A modified Trpresidue an amine group replaces a hydroxyl group at the carboxyterminus.” 42 Xaa Xaa Leu Gly Xaa 1 5 5 amino acids amino acid singlelinear peptide Modified_site 1 /label= 4F_Phe /note= “Phe residuemodified at C4 with a fluorine atom.” Modified_site 2 /label= 4Hyp/note= “Amino acid #2 is either cis_ or trans_ 4Hyp.” Modified_site 5/label= Trp_NH2 /note= “A modified Trp residue an amine group replaces ahydroxyl group at the carboxy terminus.” 43 Xaa Xaa Arg Gly Xaa 1 5 5amino acids amino acid single linear peptide Modified_site 5 /label=Trp_NH2 /note= “A modified Trp residue an amine group replaces ahydroxyl group at the carboxy terminus.” 44 Pro Ile Leu Gly Xaa 1 5 5amino acids amino acid single linear peptide Modified_site 1 /label=4Hyp /note= “Amino acid #1 is either cis_ or trans_ 4Hyp.” Modified_site5 /label= Trp_NH2 /note= “A modified Trp residue an amine group replacesa hydroxyl group at the carboxy terminus.” 45 Xaa Ile Leu Gly Xaa 1 5 6amino acids amino acid single linear peptide Modified_site 1 /label=4F_Phe /note= “Phe residue modified at C4 with a fluorine atom.”Modified_site 2 /label= 4Hyp /note= “A amino acid #2 is either cis_ ortrans_ 4Hyp.” Modified_site 6 /label= Gly_NH2 /note= “A modified Glyresidue an amine group replaces a hydroxyl group at the carboxyterminus.” 46 Xaa Xaa Ile Gly Trp Xaa 1 5 7 amino acids amino acidsingle linear peptide Modified_site 1 /label= 4F_Phe /note= “Phe residuemodified at C4 with a fluorine atom.” Modified_site 2 /label= 4Hyp/note= “Amino acid #2 is either cis_ or trans_ 4Hyp.” Modified_site 7/label= Trp_NH2 /note= “A modified Trp residue an amine group replaces ahydroxyl group at the carboxy terminus.” 47 Xaa Xaa Ile Gly Trp Gly Xaa1 5 6 amino acids amino acid single linear peptide Modified_site 1/label= 4F_Phe /note= “Phe residue modified at C4 with a fluorine atom.”Modified_site 2 /label= 4Hyp /note= “Amino acid #2 is either cis_ ortrans_ 4Hyp.” Modified_site 6 /label= Gly_NH2 /note= “A modified Glyresidue an amine group replaces a hydroxyl group at the carboxyterminus.” 48 Xaa Xaa Leu Gly Trp Xaa 1 5 7 amino acids amino acidsingle linear peptide Modified_site 1 /label= 4F_Phe /note= “Phe residuemodified at C4 with a fluorine atom.” Modified_site 2 /label= 4Hyp/note= “Amino acid #2 is either cis_ or trans_ 4Hyp.” Modified_site 7/label= Trp_NH2 /note= “A modified Trp residue an amine group replaces ahydroxyl group at the carboxy terminus.” 49 Xaa Xaa Leu Gly Trp Gly Xaa1 5 7 amino acids amino acid single linear peptide Modified_site 7/label= Gly_NH2 /note= “A modified Gly residue an amine group replaces ahydroxyl group at the carboxy terminus.” 50 Pro Ile Gly Trp Pro Ile Xaa1 5 6 amino acids amino acid single linear peptide Modified_site 1/label= 4F_Phe /note= “Phe residue modified at C4 with a fluorine atom.”Modified_site 2 /label= 4Hyp /note= “Amino acid #2 is either cis_ ortrans_ 4Hyp.” Modified_site 6 /label= Gly_NH2 /note= “A modified Glyresidue an amine group replaces a hydroxyl group at the carboxyterminus.” 51 Xaa Xaa Arg Gly Trp Xaa 1 5 7 amino acids amino acidsingle linear peptide Modified_site 1 /label= 4F_Phe /note= “Phe residuemodified at C4 with a fluorine atom.” Modified_site 2 /label= 4Hyp/note= “Amino acid #2 is either cis_ or trans_ 4Hyp.” Modified_site 7/label= Trp_NH2 /note= “A modified Trp residue an amine group replaces ahydroxyl group at the carboxy terminus.” 52 Xaa Xaa Arg Gly Trp Gly Xaa1 5 6 amino acids amino acid single linear peptide Modified_site 1/label= 4Hyp /note= “Amino acid #1 is either cis_ or trans_ 4Hyp.”Modified_site 4 /label= 4Hyp /note= “Amino acid #4 is either cis_ ortrans_ 4Hyp.” Modified_site 6 /label= Gly_NH2 /note= “A modified Glyresidue an amine group replaces a hydroxyl group at the carboxyterminus.” 53 Xaa Ile Gly Xaa Ile Xaa 1 5 4 amino acids amino acidsingle linear peptide Modified_site 4 /label= Gly_NH2 /note= “A modifiedGly residue an amine group replaces a hydroxyl group at the carboxyterminus.” 54 Tyr Pro Trp Xaa 1 5 amino acids amino acid single linearpeptide Modified_site 1 /label= 4F_Phe /note= “Phe residue modified atC4 with a fluorine atom.” Modified_site 2 /label= 3_4DeH_Pro /note=“Proline residue with a C3=C4 double bond.” Modified_site 5 /label=Trp_NH2 /note= “A modified Trp residue an amine group replaces ahydroxyl group at the carboxy terminus.” 55 Xaa Xaa Arg Gly Xaa 1 5 7amino acids amino acid single linear peptide Modified_site 1 /label=4F_Phe /note= “Phe residue modified at C4 with a fluorine atom.”Modified_site 2 /label= 4Hyp /note= “Amino acid #2 is either cis_ ortrans_ 4Hyp.” Modified_site 7 /label= Trp_NH2 /note= “A modified Trpresidue an amine group replaces a hydroxyl group at the carboxyterminus.” 56 Xaa Xaa Arg Gly Ile Gly Xaa 1 5 5 amino acids amino acidsingle linear peptide Modified_site 1 /label= 4F_Phe /note= “Phe residuemodified at C4 with a fluorine atom.” Modified_site 2 /label= Homo_Pro/note= “Amino acid #2 is Homo_Pro.” Modified_site 5 /label= Trp_NH2/note= “A modified Trp residue an amine group replaces a hydroxyl groupat the carboxy terminus.” 57 Xaa Xaa Arg Gly Xaa 1 5 6 amino acids aminoacid single linear peptide Modified_site 1 /label= 4F_Phe /note= “Pheresidue modified at C4 with a fluorine atom.” Modified_site 2 /label=4Hyp /note= “Amino acid #2 is either cis_ or trans_ 4Hyp.” Modified_site6 /label= Trp_NH2 /note= “A modified Trp residue an amine group replacesa hydroxyl group at the carboxy terminus.” 58 Xaa Xaa Arg Gly Gly Xaa 15 5 amino acids amino acid single linear peptide Modified_site 1 /label=4CH3O_Phe /note= “Phe residue modified at C4 with a methoxy group.”Modified_site 2 /label= 4Hyp /note= “Amino acid #2 is either cis_ ortrans_ 4Hyp.” Modified_site 5 /label= Trp_NH2 /note= “A modified Trpresidue an amine group replaces a hydroxyl group at the carboxyterminus.” 59 Xaa Xaa Arg Gly Xaa 1 5 4 amino acids amino acid singlelinear peptide Modified_site 1 /label= 4Cl_Phe /note= “Phe residuemodified at C4 with a chlorine atom.” Modified_site 2 /label= 4Hyp/note= “Amino acid #2 is either cis_ or trans_ 4Hyp.” Modified_site 4/label= Gly_NH2 /note= “A modified Gly residue an amine group replaces ahydroxyl group at the carboxy terminus.” 60 Xaa Xaa Ile Xaa 1 5 aminoacids amino acid single linear peptide Modified_site 1 /label= 4Cl_Phe/note= “Phe residue modified at C4 with a chlorine atom.” Modified_site2 /label= 4Hyp /note= “Amino acid #2 is either cis_ or trans_ 4Hyp.”Modified_site 5 /label= Trp_NH2 /note= “A modified Trp residue an aminegroup replaces a hydroxyl group at the carboxy terminus.” 61 Xaa Xaa ArgGly Xaa 1 5 4 amino acids amino acid single linear peptide Modified_site1 /label= 3_4DeH_Pro /note= “Proline residue with C3=C4 double bond.”Modified_site 4 /label= Trp_NH2 /note= “A modified Trp residue an aminegroup replaces a hydroxyl group at the carboxy terminus.” 62 Xaa Arg GlyXaa 1 5 amino acids amino acid single linear peptide Modified_site 1/label= 4_NH2_Phe /note= “Phe residue modified at C4 with an aminegroup.” Modified_site 2 /label= 4Hyp /note= “Amino acid #2 is eithercis_ or trans_ 4Hyp.” Modified_site 5 /label= Trp_NH2 /note= “A modifiedTrp residue an amine group replaces a hydroxyl group at the carboxyterminus.” 63 Xaa Xaa Arg Gly Xaa 1 5 5 amino acids amino acid singlelinear peptide Modified_site 1 /label= 4F_Phe /note= “Phe residuemodified at C4 with a fluorine atom.” Modified_site 2 /label= 4Hyp/note= “Amino acid #2 is either cis_ or trans_ 4Hyp.” Modified_site 5/label= Trp_NH2 /note= “A modified Trp residue an amine group replaces ahydroxyl group at the carboxy terminus.” 64 Xaa Xaa His Gly Xaa 1 5 5amino acids amino acid single linear peptide Modified_site 1 /label=4_NO2_Phe /note= “Phe residue modified at C4 with a nitro group.”Modified_site 2 /label= 4Hyp /note= “Amino acid #2 is either cis_ ortrans_ 4Hyp.” Modified_site 5 /label= Trp_NH2 /note= “A modified Trpresidue an amine group replaces a hydroxyl group at the carboxyterminus.” 65 Xaa Xaa Arg Gly Xaa 1 5 5 amino acids amino acid singlelinear peptide Modified_site 1 /label= 3F_Phe /note= “Phe residuemodified at C3 with a fluorine atom.” Modified_site 2 /label= 4Hyp/note= “Amino acid #2 is either cis_ or trans_ 4Hyp.” Modified_site 5/label= Trp_NH2 /note= “A modified Trp residue an amine group replaces ahydroxyl group at the carboxy terminus.” 66 Xaa Xaa Arg Gly Xaa 1 5 6amino acids amino acid single linear peptide Modified_site 1 /label=4F_Phe /note= “Phe residue modified at C4 with a fluorine atom.”Modified_site 2 /label= 4Hyp /note= “Amino acid #2 is either cis_ ortrans_ 4Hyp.” Modified_site 6 /label= Trp_NH2 /note= “A modified Trpresidue an amine group replaces a hydroxyl group at the carboxyterminus.” 67 Xaa Xaa Arg Ile Gly Xaa 1 5 5 amino acids amino acidsingle linear peptide Modified_site 1 /label= 2F_Phe /note= “Phe residuemodified at C2 with a fluorine atom.” Modified_site 2 /label= 4Hyp/note= “Amino acid #2 is either cis_ or trans_ 4Hyp.” Modified_site 5/label= Trp_NH2 /note= “A modified Trp residue an amine group replaces ahydroxyl group at the carboxy terminus.” 68 Xaa Xaa Arg Gly Xaa 1 5 5amino acids amino acid single linear peptide Modified_site 1 /label=4F_Phe /note= “Phe residue modified at C4 with a fluorine atom.”Modified_site 2 /label= Homo_Pro /note= “Amino acid #2 is Homo_Pro.”Modified_site 5 /label= Trp_NH2 /note= “A modified Trp residue an aminegroup replaces a hydroxyl group at the carboxy terminus.” 69 Xaa Xaa IleGly Xaa 1 5 5 amino acids amino acid single linear peptide Modified_site1 /label= 3_3_pyridyl_Ala /note= “Ala residue modified at branch methylgroup with a pyridyl group.” Modified_site 2 /label= 4Hyp /note= “Aminoacid #2 is either cis_ or trans_ 4Hyp.” Modified_site 5 /label= Trp_NH2/note= “A modified Trp residue an amine group replaces a hydroxyl groupat the carboxy terminus.” 70 Xaa Xaa Arg Gly Xaa 1 5 5 amino acids aminoacid single linear peptide Modified_site 1 /label= 4F_Phe /note= “Pheresidue modified at C4 with a fluorine atom.” Modified_site 2 /label=4Hyp /note= “Amino acid #2 is either cis_ or trans_ 4Hyp.” Modified_site3 /label= Homo_Arg /note= “Amino acid #3 is Homo_Arg.” Modified_site 5/label= Trp_NH2 /note= “A modified Trp residue an amine group replaces ahydroxyl group at the carboxy terminus.” 71 Xaa Xaa Xaa Gly Xaa 1 5 5amino acids amino acid single linear peptide Modified_site 1 /label=4F_Phe /note= “Phe residue modified at C4 with a fluorine atom.”Modified_site 2 /label= 3_4DeH_Pro /note= “Proline residue with a C3=C4double bond.” Modified_site 5 /label= Trp_NH2 /note= “A modified Trpresidue an amine group replaces a hydroxyl group at the carboxyterminus.” 72 Xaa Xaa Ile Gly Xaa 1 5 5 amino acids amino acid singlelinear peptide Modified_site 1 /label= 4F_Phe /note= “Phe residuemodified at C4 with a fluorine atom.” Modified_site 2 /label= 4Hyp/note= “Amino acid #2 is either cis_ or trans_ 4Hyp.” Modified_site 3/label= L_Allo_Ile /note= “Amino acid #3 is L_Allo_Ile.” Modified_site 5/label= Trp_NH2 /note= “A modified Trp residue an amine group replaces ahydroxyl group at the carboxy terminus.” 73 Xaa Xaa Xaa Gly Xaa 1 5 5amino acids amino acid single linear peptide Modified_site 1 /label=4F_Phe /note= “Phe residue modified at C4 with a fluorine atom.”Modified_site 2 /label= 4Hyp /note= “Amino Acid #2 is either cis_ ortrans_ 4Hyp.” Modified_site 3 /label= Homo_Arg /note= “Amino acid #3 isHomo_Arg.” 74 Xaa Xaa Xaa Gly Trp 1 5 4 amino acids amino acid singlelinear peptide Modified_site 1 /label= 4F_Phe /note= “Phe residuemodified at C4 with a fluorine atom. Modified_site 2 /label= 4Hyp /note=”Amino acid #2 is either cis_ or trans_ 4Hyp.“ Modified_site 4 /label=Gly-X /note= ”A modified Gly residue a1,2,3,4-Tetrahydroisoquinoline-3-carboxamide carbamyl group replaces thehydroxyl group at the carboxy terminus.“ 75 Xaa Xaa Arg Xaa 1 5 aminoacids amino acid single linear peptide Modified_site 1 /label=Dichloro_Phe /note= ”Phe residue modified at C3 and C4 with a chlorineatom.“ Modified_site 2 /label= 4Hyp /note= ”Amino acid #2 is either cis_or trans_ 4Hyp.“ Modified_site 5 /label= Trp_NH2 /note= ”A modified Trpresidue an amine group replaces a hydroxyl group at the carboxyterminus.“ 76 Xaa Xaa Arg Gly Xaa 1 5 5 amino acids amino acid singlelinear peptide Modified_site 1 /label= 4NC_Phe /note= ”Phe residuemodified at C4 with a nitrile group.“ Modified_site 2 /label= 4Hyp/note= ”Amino acid #2 is either cis_ or trans_ 4Hyp.“ Modified_site 5/label= Trp_NH2 /note= ”A modified Trp residue an amine group replaces ahydroxyl group at the carboxy terminus.“ 77 Xaa Xaa Arg Gly Xaa 1 5 5amino acids amino acid single linear peptide Modified_site 1 /label=4F_Phe /note= ”Phe residue modified at C4 with a fluorine atom.“Modified_site 2 /label= 4Hyp /note= ”Amino acid #2 is either cis_ ortrans_ 4Hyp.“ Modified_site 3 /label= D_Leu /note= ”Amino acid #3 isD_Leu.“ Modified_site 5 /label= Trp_NH2 /note= ”A modified Trp residuean amine group replaces a hydroxyl group at the carboxy terminus.“ 78Xaa Xaa Xaa Gly Xaa 1 5 5 amino acids amino acid single linear peptideModified_site 1 /label= 4F_Phe /note= ”Phe residue modified at C4 with afluorine atom.“ Modified_site 2 /label= 3Hyp /note= ”Amino acid #2 istrans_3_hydroxy_Pro.“ Modified_site 5 /label= Trp_NH2 /note= ”A modifiedTrp residue an amine group replaces a hydroxyl group at the carboxyterminus.“ 79 Xaa Xaa Arg Gly Xaa 1 5 6 amino acids amino acid singlelinear peptide Modified_site 1 /label= 4F_Phe /note= ”Phe residuemodified at C4 with a fluorine atom.“ Modified_site 2 /label= 3_4DeH_Pro/note= ”Proline residue with C3=C4 double bond.“ Modified_site 6 /label=Trp_NH2 /note= ”A modified Trp residue an amine group replaces ahydroxyl group at the carboxy terminus.“ 80 Xaa Xaa Arg Gly Gly Xaa 1 55 amino acids amino acid single linear peptide Modified_site 1 /label=4CH3O_Phe /note= ”Phe residue modified at C4 with a methoxy group.“Modified_site 2 /label= 3_4DeH_Pro /note= ”Proline residue with a C3=C4double bond.“ Modified_site 5 /label= Trp_NH2 /note= ”A modified Trpresidue an amine group replaces a hydroxyl group at the carboxyterminus.“ 81 Xaa Xaa Arg Gly Xaa 1 5 5 amino acids amino acid singlelinear peptide Modified_site 1 /label= 2_4DiF_Phe /note= ”Phe residuemodified at C2 and C4 with a fluorine atom.“ Modified_site 2 /label=3_4DiH_Pro /note= ”A modified proline residue a double bond is replacewith a hydrogen atom at each of C3 and C4.“ Modified_site 5 /label=Trp_NH2 /note= ”A modified Trp residue an amine group replaces ahydroxyl group at the carboxy terminus.“ 82 Xaa Xaa Arg Gly Xaa 1 5 5amino acids amino acid single linear peptide Modified_site 1 /label=4_CF3_Phe /note= ”Phe residue modified at C4 with a trifluoro methylgroup.“ Modified_site 2 /label= 3_4DeH_Pro /note= ”Proline residue withC3=C4 double bond.“ Modified_site 5 /label= Trp_NH2 /note= ”A modifiedTrp residue an amine group replaces a hydroxyl group at the carboxyterminus.“ 83 Xaa Xaa Arg Gly Xaa 1 5 5 amino acids amino acid singlelinear peptide Modified_site 1 /label= 4F-PhenylGly /note= ”A Glyresidue modified at the N-terminus with a phenyl group having a fluorineatom at C4. Modified_site 2 /label= 3_4DeH_Pro /note= “Proline residuewith C3=C4 double bond.” Modified_site 5 /label= Trp_NH2 /note= “Amodified Trp residue an amine group replaces a hydroxyl group at thecarboxy terminus.” 84 Xaa Xaa Arg Gly Xaa 1 5 5 amino acids amino acidsingle linear peptide Modified_site 1 /label= 3F_Tyr /note= “Tyr residuemodified at C3 with a fluorine atom.” Modified_site 2 /label= 3_4DeH_Pro/note= “Proline residue with C3=C4 double bond.” Modified_site 5 /label=Trp_NH2 /note= “A modified Trp residue an amine group replaces ahydroxyl group at the carboxy terminus.” 85 Xaa Xaa Arg Gly Xaa 1 5 5amino acids amino acid single linear peptide Modified_site 1 /label=4F_Phe /note= “Phe residue modified at C4 with a fluorine atom.”Modified_site 2 /label= 3_4DeH_Pro /note= “Proline residue with C3=C4double bond.” Modified_site 5 /label= Trp_NHOH /note= “A modified Trpresidue a hydroxyamino group replaces a hydroxyl group at the carboxyterminus.” 86 Xaa Xaa Arg Gly Xaa 1 5 5 amino acids amino acid singlelinear peptide Modified_site 1 /label= 3_4DiCl_Phe /note= “Phe residuemodified at C3 and C4 with a chlorine atom.” Modified_site 2 /label=3_4DiH_Pro /note= “A modified proline residue a double bond replacedwith a hydrogen atom at each of C3 and C4.” Modified_site 5 /label=Trp_NH2 /note= “A modified Trp residue an amine group replaces ahydroxyl group at the carboxy terminus.” 87 Xaa Xaa Arg Gly Xaa 1 5 5amino acids amino acid single linear peptide Modified_site 1 /label=2F_Tyr /note= “Tyr residue modified at C2 with a fluorine atom.”Modified_site 2 /label= 3_4DeH_Pro /note= “Proline residue with C3=C4double bond.” Modified_site 5 /label= Trp_NH2 /note= “A modified Trpresidue an amine group replaces a hydroxyl group at the carboxyterminus.” 88 Xaa Xaa Arg Gly Xaa 1 5 5 amino acids amino acid singlelinear peptide Modified_site 1 /label= 4F_Phe /note= “Phe residuemodified at C4 with a fluorine atom.” Modified_site 2 /label= 3_4DeH_Pro/note= “A proline residue with a C3=C4 double bond.” Modified_site 5/label= 7_AzaTrp_NH2 /note= “A modified Trp residue a nitrogen atomreplaces C7 and an amine group replaces a hydroxyl group at the carboxyterminus.” 89 Xaa Xaa Arg Gly Xaa 1 5 5 amino acids amino acid singlelinear peptide Modified_site 1 /label= 4F_Phe /note= “Phe residuemodified at C4 with a fluorine atom.” Modified_site 2 /label= 3_4DeH_Pro/note= “A proline residue with a C3=C4 double bond.” Modified_site 5/label= 4F_Trp_NH2 /note= “A modified Trp residue modified at C4 with afluorine atom and with an amine group in place of a hydroxyl group atthe carboxy terminus.” 90 Xaa Xaa Arg Gly Xaa 1 5 5 amino acids aminoacid single linear peptide Modified_site 1 /label= 4F_Phe /note= “Pheresidue modified at C4 with a fluorine atom.” Modified_site 2 /label=3_4DeH_Pro /note= “A proline residue with a C3=C4 double bond.”Modified_site 5 /label= 5F_Trp_NH2 /note= “A Trp residue modified at C5with a fluorine atom and with an amine group replacing a hydroxyl groupat the carboxy terminus.” 91 Xaa Xaa Arg Gly Xaa 1 5 5 amino acids aminoacid single linear peptide Modified_site 1 /label= 4F_Phe /note= “Pheresidue modified at C4 with a fluorine atom.” Modified_site 2 /label=3_4DiH_Pro /note= “A modified proline residue a double bond replaced bya hydrogen atom at both C3 and C4.” Modified_site 5 /label= 6F_Trp_NH2/note= “A Trp residue modified at C6 with a fluorine atom and with anamine group in place of a hydroxyl group at the carboxy terminus.” 92Xaa Xaa Arg Gly Xaa 1 5 5 amino acids amino acid single linear peptideModified_site 1 /label= 4F_Phe /note= “Phe residue modified at C4 with afluorine atom.” Modified_site 2 /label= 3_4DeH_Pro /note= “Prolineresidue with a C3=C4 double bond.” Modified_site 5 /label=3_CH3O_Trp_NH2 /note= “A Trp residue modified at C3 with a methoxy groupand with an amine group in place of a hydroxyl group at the carboxyterminus.” 93 Xaa Xaa Arg Gly Xaa 1 5 5 amino acids amino acid singlelinear peptide Modified_site 1 /label= 4F_Phe /note= “Phe residuemodified at C4 with a fluorine atom.” Modified_site 2 /label= 3_4DeH_Pro/note= “Proline residue with C3=C4 double bond.” Modified_site 5 /label=N_CH3_Trp_NH2 /note= “Trp residue modified at the hetero nitrogen with amethyl group and an amine group replaces a hydroxyl group at theC_terminus.” 94 Xaa Xaa Arg Gly Xaa 1 5 5 amino acids amino acid singlelinear peptide Modified_site 1 /label= 4F_Phe /note= “Phe residuemodified at C4 with a fluorine atom.” Modified_site 2 /label= 3_4DeH_Pro/note= “Proline residue with C3=C4 double bond.” Modified_site 5 /label=1_CH3_Trp_NH2 /note= “A Trp residue modified at C1 with a methyl groupand an amine group replaces a hydroxly group at the carboxy terminus.”95 Xaa Xaa Arg Gly Xaa 1 5 5 amino acids amino acid single linearpeptide Modified_site 1 /label= 4F_Phe /note= “Phe residue modified atC4 with a fluorine atom.” Modified_site 2 /label= 3_4DeH_Pro /note=“Proline residue with C3=C4 double bond.” Modified_site 5 /label=4_CH3_Trp_NH2 /note= “A trp residue modified at C4 with a methyl groupand an amine group replaces a hydroxyl group at the carboxy terminus.”96 Xaa Xaa Arg Gly Xaa 1 5 5 amino acids amino acid single linearpeptide Modified_site 1 /label= 4F_Phe /note= “Phe residue modified atC4 with a fluorine atom.” Modified_site 2 /label= 3_4DeH_Pro /note=“Proline residue with C3=C4 double bond.” Modified_site 5 /label=5_CH3_Trp_NH2 /note= “A Trp residue modified at C5 with a methyl groupand an amine group replaces a hydroxyl group at the carboxy terminus.”97 Xaa Xaa Arg Gly Xaa 1 5 5 amino acids amino acid single linearpeptide Modified_site 1 /label= 4F_Phe /note= “Phe residue modified atC4 with a fluorine atom.” Modified_site 2 /label= 3_4DeH_Pro /note=“Proline residue with C3=C4 double bond.” Modified_site 5 /label=6_CH3_Trp_NH2 /note= “A Trp residue modified at C6 with a methyl groupand an amine group replaces a hydroxyl group at the carboxy terminus.”98 Xaa Xaa Arg Gly Xaa 1 5 5 amino acids amino acid single linearpeptide Modified_site 1 /label= 4F_Phe /note= “Phe residue modified atC4 with a fluorine atom.” Modified_site 2 /label= 3_4DeH_Pro /note=“Proline residue with C3=C4 double bond.” Modified_site 5 /label=5_OH_Trp_NH2 /note= “A Trp residue modified at C5 with a hydroxyl groupand an amine group replaces a hydroxyl group at the carboxy terminus.”99 Xaa Xaa Arg Gly Xaa 1 5 4 amino acids amino acid single linearpeptide Modified_site 1 /label= 4F_Phe_Acid /note= “A Phe residuemodified at C4 with a fluorine atom and isonipecotic acid replaces ahydroxyl group at the carboxy terminus.” Modified_site 4 /label=Trp_NH2_complex /note= “A modified Trp residue an amine group complexedwith 4_pyridinecarboxylic acid replaces a hydroxyl group at the carboxyterminus.” 100 Xaa Arg Gly Xaa 1 4 amino acids amino acid single linearpeptide Modified_site 1 /label= 4_F_Phe_2CarbA /note= “A modified Pheresidue with a fluorine atom at C4 and with a 2_Carboxy Azetidino groupin place of a hydroxyl group at the carboxy terminus.” Modified_site 4/label= Trp_NH2 /note= “A modified Trp residue an amine group replaces ahydroxyl group at the carboxy terminus.” 101 Xaa Arg Gly Xaa 1 5 aminoacids amino acid single linear peptide Modified_site 1 /label= 4F_Phe/note= “A modified Phe residue with a fluorine atom at C4.”Modified-site 2 /label= AminoAcid /note= “Amino acid #2 is1-Amino-1-Carboxy cyclopentane.” Modified_site 4 /label= Trp_NH2 /note=“A modified Trp residue an amine group replaces a hydroxyl group at thecarboxy terminus.” 102 Xaa Xaa Arg Gly Xaa 1 5 4 amino acids amino acidsingle linear peptide Modified_site 1 /label= 4F_Phe_CAzi /note= “Amodified Phe residue with a fluorine atom at C4 and a 2_carboxyAziridino group in place of a hydroxyl group at the carboxy terminus.”Modified_site 4 /label= Trp_NH2 /note= “A modified Trp residue an aminegroup replaces a hydroxyl group at the carboxy terminus.” 103 Xaa ArgGly Xaa 1 5 amino acids amino acid single linear peptide Modified_site 1/label= 4F_Phe /note= “A modified Phe residue with a fluorine atom atC4.” Modified-site 2 /label= AminoAcid /note= “Amino acid #2 is1-Amino-1-carboxy cyclopropane.” Modified_site 4 /label= Trp_NH2 /note=“A modified Trp residue an amine group replaces a hydroxyl group at thecarboxy terminus.” 104 Xaa Xaa Arg Gly Xaa 1 5 4 amino acids amino acidsingle linear peptide Modified_site 1 /label= 4F_Phe_CTtpyr /note= “Amodified Phe residue with a fluorine atom at C4 and a3_Carboxy_1,4,5,6_Tetrahydropyridine in place of a hydroxyl group at thecarboxy terminus.” Modified_site 4 /label= Trp_NH2 /note= “A modifiedTrp residue an amine group replaces a hydroxyl group at the carboxyterminus.” 105 Xaa Arg Gly Xaa 1 4 amino acids amino acid single linearpeptide Modified_site 1 /label= 4F_Phe_Pyrrole /note= “A modified Pheresidue with a fluorine atom at C4 and a 2_carboxypyrrolyl group inplace of a hydroxyl group at the carboxy terminus.” Modified_site 4/label= Trp_NH2 /note= “A modified Trp residue an amine group replaces ahydroxyl group at the carboxy terminus.” 106 Xaa Arg Gly Xaa 1 5 aminoacids amino acid single linear peptide Modified_site 1 /label= 4F_Phe/note= “Phe residue modified at C4 with a fluorine atom.” Modified_site2 /label= 4Hyp /note= “Amino acid #2 is either cis- or trans- 4Hyp.”Modified_site 5 /label= 4F_Trp_NH2 /note= “A modified Trp residue with afluorine atom at C4 and an amine group replacing a hydroxyl group at thecarboxy terminus.” 107 Xaa Xaa Arg Gly Xaa 1 5 5 amino acids amino acidsingle linear peptide Modified_site 1 /label= 4F_Phe /note= “Phe residuemodified at C4 with a fluorine atom.” Modified_site 2 /label= 4_Hyp/note= “Amino acid #2 is either cis- or trans- 4Hyp.” Modified_site 5/label= 7_CH3_Trp_NH2 /note= “A modified Trp residue with a methyl groupat C7 and an amine group in place of a hydroxyl group at the carboxyterminus.” 108 Xaa Xaa Arg Gly Xaa 1 5 5 amino acids amino acid singlelinear peptide Modified_site 1 /label= 4F_Phe /note= “Phe residuemodified at C4 with a fluorine atom.” Modified_site 2 /label= 4Hyp/note= “Amino acid #2 is either cis- or trans- 4Hyp.” Modified_site 3/label= 5_5_5TriF_Leu /note= “Leu residue modified at C5 with threefluorine atoms.” Modified_site 5 /label= Trp_NH2 /note= “A modified Trpresidue an amine group replaces a hydroxyl group at the carboxyterminus.” 109 Xaa Xaa Xaa Gly Xaa 1 5 5 amino acids amino acid singlelinear peptide Modified_site 1 /label= 4F_Phe /note= “Phe residuemodified at C4 with a fluorine atom.” Modified_site 2 /label= 3_4DeH_Pro/note= “Proline residue with C3=C4 double bond.” Modified_site 4 /label=Sar /note= “Amino acid #4 is L_sarcosine (N_methylglycine).”Modified_site 5 /label= Trp_NH2 /note= “A modified Trp residue an aminegroup replaces a hydroxyl group at the carboxy terminus.” 110 Xaa XaaArg Xaa Xaa 1 5 5 amino acids amino acid single linear peptideModified_site 1 /label= 4F_Phe /note= “Phe residue modified at C4 with afluorine atom.” Modified_site 2 /label= 3_4DeH_Pro /note= “Prolineresidue with C3=C4 double bond.” Modified_site 4 /label= Sar /note=“Amino acid #4 is L_sarcosine (N_methylglycine).” Modified_site 5/label= Trp_NH2 /note= “A modified Trp residue an amine group replaces ahydroxyl group at the carboxy terminus.” 111 Xaa Xaa Arg Xaa Xaa 1 5 4amino acids amino acid single linear peptide Modified_site 4 /label=Gly_NH2 /note= “A modified Gly residue an amine group replaces ahydroxyl group at the carboxy terminus.” 112 Tyr Pro Leu Xaa 1 4 aminoacids amino acid single linear peptide Modified_site 1 /label= R1_AA1/note= “A Trp, Tyr or Phe residue modified with a hydrogen atom; a loweralkyl group; a halogen atom; or a hydroxyl, sulphydryl, alkylamino ordialkylamino group.” Modified_site 2 /label= R2_Pro1 /note= “A Pro ordehydro_Pro residue modified with a hydrogen atom; a lower alkyl group;a halogen atom; or a hydroxyl, sulphydryl, alkylamino or dialkylaminogroup.” Modified_site 3 /label= AA2 /note= “An amino acid of the groupLeu, Ile and Trp.” Modified_site 4 /label= Gly_R /note= “A Gly residuemodified with a carboxyl group, a hydroxyalkyl group, a carbamyl group,an alkylcarbamyl group, or an alkoxycarbonyl group at the carboxyterminus.” 113 Xaa Xaa Xaa Xaa 1 4 amino acids amino acid single linearpeptide Modified_site 1 /label= R1_AA1 /note= “A Leu, Ile or Trp residuemodified with a hydrogen atom; a lower alkyl group; a halogen; or ahydroxyl, sulphydryl, alkylamino, or dialkylamino group.” Modified_site2 /label= R2_Pro1 /note= “A Pro or dehydro_Pro residue modified with ahydrogen atom; a halogen atom; or a lower alkyl, hydroxyl, sulphydryl,alkylamino, or dialkylamino group.” Modified_site 3 /label= AA2 /note=“An amino acid of the group Leu, Ile, and Trp, with the proviso that AA2cannot be Trp if the amino acid at location 1 is a Tyr residue modifiedwith a hydrogen atom and the amino acid at location 2 is a Pro residuemodified with a hydrogen atom.” Modified_site 4 /label= Gly_NH2 /note=“A modified Gly residue an amine group replaces a hydroxyl group at thecarboxy terminus.” 114 Xaa Xaa Xaa Xaa 1 4 amino acids amino acid singlelinear peptide Modified_site 1 /label= R1_AA1 /note= “A Trp, Tyr or Pheresidue modified with a hydrogen atom; a halogen atom; or a lower alkyl,hydroxyl, sulphydryl, alkylamino or dialkylamino group.” Modified_site 2/label= R2_Pro1 /note= “”R2_Pro1 is a Pro or dehydro_Pro residuemodified with a hydrogen atom; a halogen atom; or a lower alkyl, ahydroxyl, sulphydryl, alkylamino, or dialkylamino group, wherein theN_terminus heterocyclic nitrogen ring of the Pro or dehydro-Pro residueis modified with a cis- or trans-4-OH- group.“ Modified_site 3 /label=AA2 /note= ”A amino acid of the group Leu, Ile, Trp and Arg.“Modified_site 4 /label= Gly_R /note= ”A Gly residue modified with acarboxyl, hydroxyalkyl, carbamyl, alkylcarbamyl or alkoxycarbonyl groupat the carboxy terminus.“ 115 Xaa Xaa Xaa Xaa 1 5 amino acids amino acidsingle linear peptide Modified_site 1 /label= R1_AA1 /note= ”A Phe orTyr residue modified with a hydrogen atom; a halogen atom; a loweralkyl, hydroxyl, sulphydryl, alkylamino, or dialkylamino group.“Modified_site 2 /label= AA2 /note= ”An amino acid from the group Phe andTyr.“ Modified_site 3 /label= R2_Pro1 /note= ”A Pro or dehydro_Proresidue modified with a hydrogen atom; a halogen atom; or a lower alkyl,hydroxyl, sulphydryl, alkylamino or dialkylamino group.“ Modified_site 4/label= AA3 /note= ”An amino acid from the group of Leu and Ile.“Modified_site 5 /label= Gly_R /note= ”A Gly residue modified with acarboxyl, hydroxyalkyl, carbamyl, alkylcarbamyl or alkoxycarbonyl groupat the carboxy terminus.“ 116 Xaa Xaa Xaa Xaa Xaa 1 5 5 amino acidsamino acid single linear peptide Modified_site 1 /label= R1_AA1 /note=”A Phe or Tyr residue modified with a hydrogen atom; a halogen atom; ora lower alkyl, hydroxyl, carbamyl, alkylcarbamyl, or alkoxycarbonylgroup.“ Modified_site 2 /label= AA2 /note= ”An amino acid from the groupPhe and Tyr.“ Modified_site 3 /label= R2_Pro1 /note= ”A Pro ordehydro_Pro residue modified with a hydrogen atom; a halogen atom; or alower alkyl, hydroxyl, sulphydryl, alkylamino or dialkylamino group.“Modified_site 4 /label= AA3 /note= ”An amino acid of the group Leu andIle.“ Modified_site 5 /label= Gly_NH2 /note= ”A modified Gly residue anamine group replaces a hydroxyl group at the carboxy terminus.“ 117 XaaXaa Xaa Xaa Xaa 1 5 5 amino acids amino acid single linear peptideModified_site 1 /label= R1_Pro1 /note= ”A Pro or dehydro_Pro residuemodified with a hydrogen atom; a halogen atom; or a lower alkyl,hydroxyl, sulphydryl, alkylamino or dialkylamino group.“ Modified_site 2/label= AA1 /note= ”An amino acid from the group Leu and Ile.“Modified_site 3 /label= AA2 /note= ”An amino acid from the group Leu andIle.“ Modified_site 5 /label= AA3_R /note= ”A Trp residue modified atthe carboxy terminus with a carboxyl, hydroxyalkyl, carbamyl,alkylcarbamyl or alkoxycarbonyl group.“ 118 Xaa Xaa Xaa Gly Xaa 1 5 5amino acids amino acid single linear peptide Modified_site 1 /label=R1_Pro1 /note= ”A Pro or dehydro_Pro residue modified with a hydrogenatom; a halogen atom; or a lower alkyl, hydroxyl, sulphydryl,alkylamino, or dialkylamino group.“ Modified_site 2 /label= AA1 /note=”An amino acid from the group Leu and Ile.“ Modified_site 3 /label= AA2/note= ”An amino acid from the group Leu and Ile.“ Modified_site 5/label= Trp_NH2 /note= ”A modified Trp residue an amine group replaces ahydroxyl group at the carboxy terminus.“ 119 Xaa Xaa Xaa Gly Xaa 1 5 4amino acids amino acid single linear peptide Modified_site 1 /label=R1_Phe /note= ”A Phe residue modified with a halogen atom.“Modified_site 2 /label= R2_Arg /note= ”An Arg residue modified with acarboxylic acid of a monocyclic organic compound with a three to sixmembered ring structure having a hetero nitrogen atom.“ Modified_site 4/label= Trp_NH2 /note= ”A modified Trp residue an amine group replaces ahydroxyl group at the carboxy terminus.“ 120 Xaa Xaa Gly Xaa 1 4 aminoacids amino acid single linear peptide Modified_site 1 /label= R1_Phe/note= ”A Phe residue modified with a halogen atom, a carboxyl group, anamino group, or a nitro group.“ Modified_site 2 /label= Pro1 /note= ”Anamino acid from the group of 3,4_dehydro Pro, Homo_Pro, cis_ ortrans_4_OH_Pro, or Pro.“ Modified_site 3 /label= AA2 /note= ”An aminoacid from the group of Ile, Leu and Arg.“ Modified_site 4 /label=AA3_NH2 /note= ”A modified Gly or Trp residue an amine group replaces ahydroxyl group at the carboxy terminus.“ 121 Xaa Xaa Xaa Xaa 1 5 aminoacids amino acid single linear peptide Modified_site 1 /label= R1_Phe/note= ”A Phe residue modified with a halogen atom.“ Modified_site 2/label= AA1 /note= ”An amino acid from the group1_amino_1_carboxycyclopentane and 1_amino_1_carboxy_cyclopropyl.“Modified_site 5 /label= Trp_NH2 /note= ”A modified Trp residue an aminegroup replaces a hydroxyl group at the carboxy terminus.“ 122 Xaa XaaArg Gly Xaa 1 5 5 amino acids amino acid single linear peptideModified_site 1 /label= R1_AA1 /note= ”A Phe residue modified withhydrogen atom, a halogen atom, or a hydroxyl group.“ Modified_site 2/label= R2_Pro1 /note= ”A Pro residue modified with a hydrogen atom, ahalogen atom or a hydroxyl group.“ Modified_site 3 /label= AA2 /note=”The amino acid homo_Arg.“ 123 Xaa Xaa Xaa Gly Trp 1 5 5 amino acidsamino acid single linear peptide Modified_site 1 /label= R1_AA1 /note=”A Phe, PhenylGly or Tyr residue modified with a hydrogen atom; at leastone halogen atom; or a lower alkyl, hydroxyl, sulphydryl, alkylamino, ordiakylamino group.“ Modified_site 2 /label= R2_Pro1 /note= ”A Pro ordehydro_Pro residue modified with a hydrogen atom; at least one halogenatom; or a lower alkyl, hydroxyl, sulphydryl, alkylamino, or diakylaminogroup.“ Modified_site 5 /label= AA3_R /note= ”A Trp or AzaTrp residuemodified with an amino group or a hydroxylamino group.“ 124 Xaa Xaa ArgGly Xaa 1 5 5 amino acids amino acid single linear peptide Modified_site1 /label= R1_AA1 /note= ”A Phe residue modified with a hydrogen atom, atleast one halogen atom or a hydroxyl group.“ Modified_site 2 /label=R2_Pro1 /note= ”A Pro residue modified with a hydrogen atom, at leastone halogen atom or a hydroxyl group.“ Modified_site 5 /label=R4_Trp_NH2 /note= ”A Trp residue modified at one of C4, C5, C6 or C7with a halogen atom, a hydroxyl group or an alkyl group and modified atthe carboxy terminus where an amine group replaces a hydroxyl group.“125 Xaa Xaa Arg Gly Xaa 1 5 5 amino acids amino acid single linearpeptide Modified_site 1 /label= R1_AA1 /note= ”A Phe residue modifiedwith a hydrogen atom, at least one halogen atom or a hydroxyl group.“Modified_site 2 /label= R2_Pro1 /note= ”A Pro residue modified with ahydrogen atom, at least one halogen atom or a hydroxyl group.“Modified_site 3 /label= R5_AA2 /note= ”A Leu residue modified with atleast one halogen atom.“ Modified_site 5 /label= Trp_NH2 /note= ”Amodified Trp residue an amine group replaces a hydroxyl group at thecarboxy terminus.“ 126 Xaa Xaa Xaa Gly Xaa 1 5 5 amino acids amino acidsingle linear peptide Modified_site 1 /label= R1_AA1 /note= ”A Pheresidue modified with a hydrogen atom or at least one halogen atom.“Modified_site 2 /label= R2_Pro1 /note= ”A Pro or dehydro_Pro residuemodified with a hydrogen atom or at least one halogen atom.“Modified_site 4 /label= Gly_R4 /note= ”A Gly residue modified with atleast one halogen, a hydroxyl group, a methyl group, or a methoxygroup.“ Modified_site 5 /label= AA3_R /note= ”A Trp residue modifiedwith a carboxyl group, a hydroxyalkyl group, a carbamyl group, analkylcarbamyl group, or an alkoxycarbonyl group.“ 127 Xaa Xaa Arg XaaXaa 1 5 6 amino acids amino acid single linear peptide Modified_site 1/label= R1_AA1 /note= ”A Phe residue modified with a hydrogen atom; ahalogen atom; or a lower alkyl, hydroxyl, sulphydryl, alkylamino, ordialkylamino group.“ Modified_site 2 /label= R2_Pro1 /note= ”Adehydro_Pro residue modified with a hydrogen atom a halogen atom; or alower alkyl, hydroxyl, sulphydryl, alkylamino, or dialkylamino group.“Modified_site 6 /label= AA3_R /note= ”A Trp residue modified with acarboxyl group, a hydoxyalkyl group, a carbamyl group, an alkylcarbamylgroup, or an alkoxycarbonyl group.“ 128 Xaa Xaa Arg Gly Gly Xaa 1 5

What is claimed is:
 1. A method for treating a physiological,psychosomatic, neurological or psychiatric disorder in a patient,comprising administering to the patient at least one tetrapeptide orsalt thereof having a general formula (5b): R¹-AA¹-R²-Pro¹-AA²-Gly-R³  (5b) wherein Pro¹ represents Pro; AA¹ represents the amino acid Phe;AA² represents the amino acid Arg; R¹ and R² are each independentlyselected from the group consisting of a hydrogen atom, a lower alkylgroup having 1 to 3 carbon atoms, a halogen atom, a hydroxyl group, asulphydryl group, an alkylamino group, and a dialkylamino group, and R³is a carbamyl group.
 2. The method of claim 1, wherein the tetrapeptideis selected from the group consisting of 4-F-Phe-cis- ortrans-4-OH-Pro-Arg-Gly-1,2,3,4-Tetrahydroisoquinoline-3-carboxamide (SEQNO: 75) and pharmaceutically acceptable salts thereof.
 3. A method fortreating a physiological, psychosomatic, neurological or psychiatricdisorder in a patient, comprising administering to the patient at leastone pentapeptide or salt thereof having a general formula (7b):R¹-AA¹-R²-Pro¹-AA²-Gly-Trp-NH₂   (7b) wherein Pro¹ represents the aminoacid Pro; AA¹ represents the amino acid Phe; AA² represents an aminoacid selected from the group consisting of D-Leu and Arg; and R¹ and R²each independently are selected from the group consisting of a hydrogenatom, a lower alkyl group having 1 to 3 carbon atoms, at least onehalogen atom, a hydroxyl group, a sulphydryl group, an alkylamino group,a diakylamino group, and a cyano group.
 4. The method of claim 3,wherein the pentapeptide is selected from the group consisting of:3,4-Dichloro-Phe-cis- or trans-4-OH-Pro-Arg-Gly-Trp-NH₂; (SEQ NO:76)4-NC-Phe-cis- or trans-4-OH-Pro-Arg-Gly-Trp-NH₂; (SEQ NO:77)4-F-Phe-cis- or trans-4-OH-Pro-D-Leu-Gly-Trp-NH₂; (SEQ NO:78)4-F-Phe-trans-3-OH-Pro-Arg-Gly-Trp-NH₂; and, (SEQ NO:79)

pharmaceutically acceptable salts thereof.
 5. A method for treating aphysiological, psychosomatic, neurological or psychiatric disorder in apatient, comprising administering to the patient at least onepentapeptide or salt thereof having a general formula (7c):R¹-AA¹-R²-Pro¹-AA²-Gly-Trp   (7c) wherein Pro¹ represents the amino acidPro; AA¹ represents the amino acid Phe; AA² represents the amino acidhomo-Arg; and R¹ and R² each independently are selected from the groupconsisting of a hydrogen atom, a halogen atom, and a hydroxyl group. 6.The method of claim 5, wherein the pentapeptide is selected from thegroup consisting of: 4-F-Phe-cis- or trans-4-OH-Pro-Homo-Arg-Gly-Tip(SEQ NO: 74); and, pharmaceutically acceptable salts thereof.
 7. Amethod for treating a physiological, psychosomatic, neurological orpsychiatric disorder in a patient, comprising administering to thepatient at least one pentapeptide or salt thereof having a generalformula (7d): R¹-AA¹-R²-Pro¹-AA²-Gly-AA³-R   (7d) wherein Pro¹represents an amino acid selected from the group consisting of Pro andDehydro-Pro; AA¹ represents an amino acid selected from the groupconsisting of Phe, PhenylGly and Tyr; AA² represents the amino acid Arg;AA³ represents an amino acid selected from the group consisting of Trpand AzaTrp; R¹ and R² each independently are selected from the groupconsisting of a hydrogen atom, a lower alkyl group having 1 to 3 carbonatoms, at least one halogen atom, a hydroxyl group, a sulphydryl group,an alkylamino group, and a diakylamino group, and R is selected from thegroup consisting of an amino group and a hydroxylamino group.
 8. Themethod of claim 7, wherein the pentapeptide is selected from the groupconsisting of: (SEQ NO:80) 4-F-Phe-3,4-Dehydro-Pro-Arg-Gly-Trp-NH₂; (SEQNO:81) 4-CH₃O-Phe-3,4-Dehydro-Pro-Arg-Gly-Trp-NH₂; (SEQ NO:82)2,4-Di-F-Phe-3,4-Dihydro-Pro-Arg-Gly-Trp-NH₂; (SEQ NO:83)4-CF₃-Phe-3,4-Dehydro-Pro-Arg-Gly-Trp-NH₂; (SEQ NO:84)4-F-PhenylGly-3,4-Dehydro-Pro-Arg-Gly-Trp-NH₂; (SEQ NO:85)3-F-Tyr-3,4-Dehydro-Pro-Arg-Gly-Trp-NH₂; (SEQ NO:86)4-F-Phe-3,4-Dehydro-Pro-Arg-Gly-Trp-NHOH; (SEQ NO:87)3,4-Di-Cl-Phe-3,4-Dihydro-Pro-Arg-Gly-Trp-NH₂; (SEQ NO:88)2-F-Tyr-3,4-Dehydro-Pro-Arg-Gly-Trp-NH₂; (SEQ NO:89)4-F-Phe-3,4-Dehydro-Pro-Arg-Gly-7-AzaTrp-NH₂; and,

pharmaceutically acceptable salts thereof.
 9. A method for treating aphysiological, psychosomatic, neurological or psychiatric disorder in apatient, comprising administering to the patient at least onepentapeptide or salt thereof having a general formula (7e):R¹-AA¹-R²-Pro¹-AA²-Gly-R⁴-Trp-NH₂   (7e) wherein Pro¹ represents theamino acid Pro; AA¹ represents the amino acid Phe; AA² represents theamino acid Arg; R¹ and R² each independently are selected from the groupconsisting of a hydrogen atom, at least one halogen atom and a hydroxylgroup; and the tryptophan residue is modified at one of C4, C5, C6 andC7, with R⁴ selected from the group consisting of a halogen atom, ahydroxyl group, and an alkyl group.
 10. The method of claim 9, whereinthe pentapeptide is selected from the group consisting of: 4-F-Phe-cis-or trans-4-OH-Pro-Arg-Gly-4-F-Trp-NH₂ (SEQ NO: 107); 4-F-Phe-cis- ortrans-4-OH-Pro-Arg-Gly-7-Methyl-Trp-NH₂ (SEQ NO: 108); and,pharmaceutically acceptable salts thereof.
 11. A method for treating aphysiological, psychosomatic, neurological or psychiatric disorder in apatient, comprising administering to the patient at least onepentapeptide or salt thereof having a general formula (7f):R¹-AA¹-R²-Pro¹-R⁵-AA²-Gly-Trp-NH₂   (7f) wherein Pro¹ represents theamino acid Pro; AA¹ represents the amino acid Phe; AA² represents theamino acid Leu; R¹ and R² each independently are selected from the groupconsisting of a hydrogen atom, at least one halogen atom and a hydroxylgroup; and R⁵ represents at least one halogen atom.
 12. The method ofclaim 11, wherein the pentapeptide is selected from the group consistingof 4-F-Phe-cis- or trans-4-OH-Pro-5,5,5-Trifluoro-Leu-Gly-Trp-NH₂ (SEQNO: 109); and pharmaceutically acceptable salts thereof.
 13. A methodfor treating a physiological, psychosomatic, neurological or psychiatricdisorder in a patient, comprising administering to the patient at leastone pentapeptide or salt thereof having a general formula (7g):R¹-AA¹-R²-Pro¹-AA²-Gly-R⁴-AA³-R   (7g) wherein Pro¹ represents an aminoacid selected from the group consisting of Pro and Dehydro-Pro; AA¹represents the amino acid Phe; AA² represents the amino acid Arg; AA³represents the amino acid Trp; R¹ and R² each independently are selectedfrom the group consisting of a hydrogen atom and at least one halogenatom; and R⁴ is selected from the group consisting of at least onehalogen atom, a hydroxyl group, a methyl group, and a methoxy group. 14.The method of claim 13, wherein the pentapeptide is selected from thegroup consisting of: (SEQ NO:90)4-F-Phe-3,4-Dehydro-Pro-Arg-Gly-4-F-Trp-NH₂; (SEQ NO:91)4-F-Phe-3,4-Dehydro-Pro-Arg-Gly-5-F-Trp-NH₂; (SEQ NO:92)4-F-Phe-3,4-Dihydro-Pro-Arg-Gly-6-F-Trp-NH₂; (SEQ NO:93)4-F-Phe-3,4-Dehydro-Pro-Arg-Gly-3-CH₃O-Trp-NH₂; (SEQ NO:94)4-F-Phe-3,4-Dehydro-Pro-Arg-Gly-N-Methyl-Trp-NH₂; (SEQ NO:95)4-F-Phe-3,4-Dehydro-Pro-Arg-Gly-1-Methyl-Trp-NH₂; (SEQ NO:96)4-F-Phe-3,4-Dehydro-Pro-Arg-Gly-4-Methyl-Trp-NH₂; (SEQ NO:97)4-F-Phe-3,4-Dehydro-Pro-Arg-Gly-5-Methyl-Trp-NH₂; (SEQ NO:98)4-F-Phe-3,4-Dehydro-Pro-Arg-Gly-6-Methyl-Trp-NH₂; (SEQ NO:99)4-F-Phe-3,4-Dehydro-Pro-Arg-Gly-5-Hydroxy-Trp-NH₂; and,

pharmaceutically acceptable salts thereof.
 15. A method for treating aphysiological, psychosomatic, neurological or psychiatric disorder in apatient, comprising administering to the patient at least onepentapeptide or salt thereof having a general formula (12):R¹-Phe-R²-Arg-Gly-Trp-NH₂   (12) wherein R¹ represents a halogen atomand R² represents a carboxylic acid of a monocyclic organic compound,with a three to six member ring structure having a hetero nitrogen atom.16. The method of claim 15, wherein the pentapeptide is selected fromthe group consisting of: 4-F-Phe-isonipecoticacid-Arg-Gly-Trp-NH₂(4-pyridinecarboxylic acid) (SEQ NO: 100);4-F-Phe-2-Carboxy-Azetidine-Arg-Gly-Trp-NH₂ (SEQ NO: 101);4-F-Phe-2-carboxy-Aziridine-Arg-Gly-Trp-NH₂ (SEQ NO: 103);4-F-Phe-3-Carboxy-1,4,5,6-Tetrahydropyridine-Arg-Gly-Trp-NH₂ (SEQ NO:105); 4-F-Phe-2-Carboxypyrrole-Arg-Gly-Trp-NH₂ (SEQ NO: 106); and,pharmaceutically acceptable salts thereof.
 17. A method for treating aphysiological, psychosomatic, neurological or psychiatric disorder in apatient, comprising administering to the patient at least onepentapeptide or salt thereof having a general formula (13):R¹-Phe-AA¹-Arg-Gly-Trp-NH₂   (13) wherein R¹ represents a halogen atom,and AA¹ represents an amino acid selected from the group consisting of1-amino-1-carboxycyclopentane and 1-amino-1-carboxycyclopropane.
 18. Themethod of claim 17, wherein the pentapeptide is selected from the groupconsisting of: 4-F-Phe-1-Amino-1-Carboxycyclopentane-Arg-Gly-Trp-NH₂;(SEQ NO:102) 4-F-Phe-1-Amino-1-Carboxy-Cyclopropyl-Arg-Gly-Trp-NH₂; (SEQNO:104) 4-F-Phe-3,4-Dehydro-Pro-Arg-Sar-Trp-NH₂; and (SEQ NO:110)

pharmaceutically acceptable salts thereof.
 19. A method for treating aphysiological, psychosomatic, neurological or psychiatric disorder in apatient, comprising administering to the patient at least one apentapeptide having a general formula (10):R¹-AA¹-R²-Pro¹-AA²-AA⁴-Gly-AA³R   (10) where Pro¹ represents the aminoacid dehydro-Pro; AA¹ represents the amino acid Phe; AA² represents theamino acid Arg; AA³ represents the amino acid Trp; AA⁴ represents theamino acid Gly; R is selected from the group consisting of a carboxylgroup, a hydroxyalkyl group, a carbamyl group, an alkylcarbamyl group,and an alkoxycarbonyl group; and, R¹ and R² each independently areselected from the group consisting of a hydrogen atom, a lower alkylgroup, a halogen atom, a hydroxyl group, a sulphydryl group, analkylamino and a dialkylamino group.
 20. The method of claim 19, whereinthe pentapeptide is selected from the group consisting of:4-F-Phe-3,4-Dehydro-Pro-Arg-Gly-Gly-Trp-NH₂ (SEQ NO: 80); and,pharmaceutically acceptable salts thereof.
 21. A method for treating aphysiological, psychosomatic, neurological or psychiatric disorder in apatient, comprising administering to the patient at least one peptideselected from the group consisting of: 4-F-Phe-cis- ortrans-4-OH-Pro-Homo-Arg-Gly-Trp; (SEQ NO:74) 4-F-Phe-cis- ortrans-4-OH-Pro-Arg-Gly-1,2,3,4-Tetrahydroisoquinoline-3-carboxamide;(SEQ NO:75) 3,4-Dichloro-Phe-cis- or trans-4-OH-Pro-Arg-Gly-Trp-NH₂;(SEQ NO:76) 4-NC-Phe-cis- or trans-4-OH-Pro-Arg-Gly-Trp-NH₂; (SEQ NO:77)4-F-Phe-cis- or trans-4-OH-Pro-D-Leu-Gly-Trp-NH₂; (SEQ NO:78)4-F-Phe-trans-3-OH-Pro-Arg-Gly-Trp-NH₂; (SEQ NO:79)4-F-Phe-3,4-Dehydro-Pro-Arg-Gly-Trp-NH₂; (SEQ NO:80)4-CH₃O-Phe-3,4-Dehydro-Pro-Arg-Gly-Trp-NH₂; (SEQ NO:81)2,4-Di-F-Phe-3,4-Dihydro-Pro-Arg-Gly-Trp-NH₂; (SEQ NO:82)4-CF₃-Phe-3,4-Dehydro-Pro-Arg-Gly-Trp-NH₂; (SEQ NO:83)4-F-PhenylGly-3,4-Dehydro-Pro-Arg-Gly-Trp-NH₂; (SEQ NO:84)3-F-Tyr-3,4-Dehydro-Pro-Arg-Gly-Trp-NH₂; (SEQ NO:85)4-F-Phe-3,4-Dehydro-Pro-Arg-Gly-Trp-NHOH; (SEQ NO:86)3,4-Di-Cl-Phe-3,4-Dihydro-Pro-Arg-Gly-Trp-NH₂; (SEQ NO:87)2-F-Tyr-3,4-Dehydro-Pro-Arg-Gly-Trp-NH₂; (SEQ NO:88)4-F-Phe-3,4-Dehydro-Pro-Arg-Gly-7-AzaTrp-NH₂; (SEQ NO:89)4-F-Phe-3,4-Dehydro-Pro-Arg-Gly-4-F-Trp-NH₂; (SEQ NO:90)4-F-Phe-3,4-Dehydro-Pro-Arg-Gly-5-F-Trp-NH₂; (SEQ NO:91)4-F-Phe-3,4-Dihydro-Pro-Arg-Gly-6-F-Trp-NH₂; (SEQ NO:92)4-F-Phe-3,4-Dehydro-Pro-Arg-Gly-3-CH₃O-Trp-NH₂; (SEQ NO:93)4-F-Phe-3,4-Dehydro-Pro-Arg-Gly-N-Methyl-Trp-NH₂; (SEQ NO:94)4-F-Phe-3,4-Dehydro-Pro-Arg-Gly-1-Methyl-Trp-NH₂; (SEQ NO:95)4-F-Phe-3,4-Dehydro-Pro-Arg-Gly-4-Methyl-Trp-NH₂; (SEQ NO:96)4-F-Phe-3,4-Dehydro-Pro-Arg-Gly-5-Methyl-Trp-NH₂; (SEQ NO:97)4-F-Phe-3,4-Dehydro-Pro-Arg-Gly-6-Methyl-Trp-NH₂; (SEQ NO:98)4-F-Phe-3,4-Dehydro-Pro-Arg-Gly-5-Hydroxy-Trp-NH₂; (SEQ NO:99)4-F-Phe-isonipecotic acid-Arg-Gly-Trp-NH₂(4-pyridinecarboxylic acid);(SEQ NO:100) 4-F-Phe-2-Carboxy-Azetidine-Arg-Gly-Trp-NH₂; (SEQ NO:101)4-F-Phe-1-Amino-1-Carboxycyclopentane-Arg-Gly-Trp-NH₂; (SEQ NO:102)4-F-Phe-2-carboxy-Aziridine-Arg-Gly-Trp-NH₂; (SEQ NO:103)4-F-Phe-1-Amino-1-Carboxy-Cyclopropyl-Arg-Gly-Trp-NH₂; (SEQ NO:104)4-F-Phe-3-Carboxy-1,4,5,6-Tetrahydropyridine-Arg-Gly-Trp-NH₂; (SEQNO:105) 4-F-Phe-2-Carboxypyrrole-Arg-Gly-Trp-NH₂; (SEQ NO:106)4-F-Phe-cis- or trans-4-OH-Pro-Arg-Gly-4-F-Trp-NH₂; (SEQ NO:107)4-F-Phe-cis- or trans-4-OH-Pro-Arg-Gly-7-Methyl-Trp-NH₂; (SEQ NO:108)4-F-Phe-cis- or trans-4-OH-Pro-5,5,5-Trifluoro-Leu-Gly-Trp-NH₂; (SEQNO:109) 4-F-Phe-3,4-Dehydro-Pro-Arg-Sar-Trp-NH₂; and, (SEQ NO:110)

pharmaceutically acceptable salts thereof.
 22. The method of any ofclaims 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 or 21, wherein said disorder isselected from the group consisting of bipolar disorder, seasonalaffective disorder, bulimia, anorexia nervosa, exogenous obesity,chronic fatigue syndrome, fibromyalgia, sexual dysfunction, anxietydisorder, attention deficit disorder, Parkinson's disease,schizophrenia, jet lag syndrome and addiction disorders.
 23. The methodof any of claims 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 or 21, wherein saiddisorder is alcohol dependency.
 24. The method of any of claims 1, 3, 5,7, 9, 11, 13, 15, 17, 19 or 21, wherein said disorder is refractorydepression.
 25. The method of any of claims 1, 3, 5, 7, 9, 11, 13, 15,17, 19 or 21, wherein said disorder is a psychosomatic disorder.
 26. Themethod of any of claims 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 or 21, whereinsaid disorder is anxiety.
 27. The method of claim 26, wherein saidanxiety is accompanied by depression.
 28. A method for treating fortreating a physiological, psychosomatic, neurological or psychiatricdisorder in a patient comprising administering to the patient one ormore peptide compounds that bind to at least one receptor selected fromthe group consisting of 5-HT and neuropeptide Y receptors in the brainof the patient.
 29. A method of any of claims 1, 3, 5, 7, 9, 11, 13, 15,17, 19, 21 or 28 wherein said administering is by a route selected fromthe group consisting of oral, sublingual, parenteral, epicutaneous,transdermal, intranasal, vaginal, rectal, and by inhalation.
 30. Amethod of claim 29 wherein said administering is parenteral and saidparenteral administration is selected from the group consisting ofintravenous, intraspinal, intrathecal, intraventricular, epidermal,intracisternal, intracutaneous, intradermal, subcutaneous, andintramuscular.
 31. A method of claim 29 wherein said administering is bya route selected from the group consisting of sublingual, epicutaneous,transdermal, intranasal, vaginal, rectal, and by inhalation.
 32. Amethod for treating for treating a physiological, psychosomatic,neurological or psychiatric disorder in a patient comprisingadministering to the patient one or more peptide compounds that aremetabolized at least in part via the serotonergic pathway of thepatient.
 33. A method for treating a physiological, psychosomatic,neurological or psychiatric disorder in a patient, comprisingadministering to the patient a peptide having the formulaPro-Leu-Gly-NH₂, wherein such administration comprises administration bya route selected from the group consisting of oral, sublingual,parenteral, epicutaneous, transdermal, intranasal, vaginal, rectal, andby inhalation.